Inhibitors of akt activity

ABSTRACT

Invented are novel heterocyclic carboxamide compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.

This application claims the benefit of U.S. Provisional Application No.60/888,586 filed Feb. 7, 2007.

FIELD OF THE INVENTION

This invention relates to novel heterocyclic carboxamide compounds, theuse of such compounds as inhibitors of protein kinase B (hereinafterPKB/Akt, PKB or Akt) activity and in the treatment of cancer andarthritis.

BACKGROUND OF THE INVENTION

The present invention relates to heterocyclic carboxamide containingcompounds that are inhibitors of the activity of one or more of theisoforms of the serine/threonine kinase, Akt (also known as proteinkinase B), suitably the compounds of the invention are inhibitors of theactivity of all three isoforms of the serine/threonine kinase, Akt. Thepresent invention also relates to pharmaceutical compositions comprisingsuch compounds and methods of using the instant compounds in thetreatment of cancer and arthritis (Liu et al. Current Opin. Pharmacology3:317-22 (2003)).

Apoptosis (programmed cell death) plays essential roles in embryonicdevelopment and pathogenesis of various diseases, such as degenerativeneuronal diseases, cardiovascular diseases and cancer. Recent work hasled to the identification of various pro- and anti-apoptotic geneproducts that are involved in the regulation or execution of programmedcell death. Expression of anti-apoptotic genes, such as Bcl2 orBcl-x_(L), inhibits apoptotic cell death induced by various stimuli. Onthe other hand, expression of pro-apoptotic genes, such as Bax or Bad,leads to programmed cell death (Adams et al. Science, 281:1322-1326(1998)). The execution of programmed cell death is mediated by caspase-1related proteinases, including caspase-3, caspase-7, caspase-8 andcaspase-9 etc (Thornberry et al. Science, 281:1312-1316 (1998)).

The phosphatidylinositol 3′-OH kinase (PI3K)/Akt/PKB pathway appearsimportant for regulating cell survival/cell death (Kulik et al. Mol.Cell. Biol. 17:1595-1606 (1997); Franke et al, Cell, 88:435-437 (1997);Kauffmann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science,275:628-630 (1997); Dudek et al., Science, 275:661-665 (1997)). Survivalfactors, such as platelet derived growth factor (PDGF), nerve growthfactor (NGF) and insulin-like growth factor-1 (IGF-1), promote cellsurvival under various conditions by inducing the activity of PI3K(Kulik et al. 1997, Hemmings 1997). Activated PI3K leads to theproduction of phosphatidylinositol (3,4,5)-triphosphate (Ptdlns(3,4,5)-P3), which in turn binds to, and promotes the activation of, theserine/threonine kinase Akt, which contains a pleckstrin homology(PH)-domain (Franke et al Cell, 81:727-736 (1995); Hemmings Science,277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998),Alessi et al., EMBO J. 15: 6541-6551 (1996)). Specific inhibitors ofPI3K or dominant negative Akt/PKB mutants abolish survival-promotingactivities of these growth factors or cytokines. It has been previouslydisclosed that inhibitors of PI3K (LY294002 or wortmanin) blocked theactivation of Akt/PKB by upstream kinases. In addition, introduction ofconstitutively active PI3K or Akt/PKB mutants promotes cell survivalunder conditions in which cells normally undergo apoptotic cell death(Kulik et al. 1997, Dudek et al. 1997).

Analysis of Akt levels in human tumors showed that Akt2 is overexpressedin a significant number of ovarian (J. Q. Cheung et al. Proc. Natl.Acad. Sci. U.S.A. 89:9267-9271 (1992)) and pancreatic cancers (J. Q.Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 93:3636-3641 (1996)).Similarly, Akt3 was found to be overexpressed in breast and prostatecancer cell lines (Nakatani et al. J. Biol. Chem. 274:21528-21532(1999). It was demonstrated that Akt-2 was over-expressed in 12% ofovarian carcinomas and that amplification of Akt was especially frequentin 50% of undifferentiated tumors, suggestion that Akt may also beassociated with tumor aggressiveness (Bellacosa, et al., Int. J. Cancer,64, pp. 280-285, 1995). Increased Akt1 kinase activity has been reportedin breast, ovarian and prostate cancers (Sun et al., Am. J. Pathol. 159:431-7 (2001)).

The tumor suppressor PTEN, a protein and lipid phosphatase thatspecifically removes the 3′ phosphate of Ptdlns(3,4,5)-P3, is a negativeregulator of the PI3K/Akt pathway (Li et al. Science 275:1943-1947(1997), Stambolic et al. Cell 95:29-39 (1998), Sun et al. Proc. Natl.Acad. Sci. U.S.A. 96:6199-6204 (1999)). Germline mutations of PTEN areresponsible for human cancer syndromes such as Cowden disease (Liaw etal. Nature Genetics 16:64-67 (1997)). PTEN is deleted in a largepercentage of human tumors and tumor cell lines without functional PTENshow elevated levels of activated Akt (Li et al. supra, Guldberg et al.Cancer Research 57:3660-3663 (1997), Risinger et al. Cancer Research57:4736-4738 (1997)).

These observations demonstrate that the PI3K/Akt pathway plays importantroles for regulating cell survival or apoptosis in tumorigenesis.

Three members of the Akt/PKB subfamily of second-messenger regulatedserine/threonine protein kinases have been identified and termedAkt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ respectively. The isoforms arehomologous, particularly in regions encoding the catalytic domains.Akt/PKBs are activated by phosphorylation events occurring in responseto PI3K signaling. PI3K phosphorylates membrane inositol phospholipids,generating the second messengers phosphatidyl-inositol3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate, whichhave been shown to bind to the PH domain of Akt/PKB. The current modelof Akt/PKB activation proposes recruitment of the enzyme to the membraneby 3′-phosphorylated phosphoinositides, where phosphorylation of theregulatory sites of Akt/PKB by the upstream kinases occurs (B. A.Hemmings, Science 275:628-630 (1997); B. A. Hemmings, Science 276:534(1997); J. Downward, Science 279:673-674 (1998)).

Phosphorylation of Akt1/PKBα occurs on two regulatory sites, Thr^(3O8)in the catalytic domain activation loop and on Ser⁴⁷³ near the carboxyterminus (D. R. Alessi et al. EMBO J. 15:6541-6551 (1996) and R. Meieret al. J. Biol. Chem. 272:30491-30497 (1997)). Equivalent regulatoryphosphorylation sites occur in Akt2/PKBβ and Akt3/PKBγ. The upstreamkinase, which phosphorylates Akt/PKB at the activation loop site hasbeen cloned and termed 3′-phosphoinositide dependent protein kinase 1(PDK1). PDK1 phosphorylates not only Akt/PKB, but also p70 ribosomal S6kinase, p90RSK, serum and glucocorticoid-regulated kinase (SGK), andprotein kinase C. The upstream kinase phosphorylating the regulatorysite of Akt/PKB near the carboxy terminus has not been identified yet,but recent reports imply a role for the integrin-linked kinase (ILK-1),a serine/threonine protein kinase, or autophosphorylation.

Inhibition of Akt activation and activity can be achieved by inhibitingPI3K with inhibitors such as LY294002 and wortmanin. However, PI3Kinhibition has the potential to indiscriminately affect not just allthree Akt isozymes but also other PH domain-containing signalingmolecules that are dependent on Pdtlns(3,4,5)-P3, such as the Tec familyof tyrosine kinases. Furthermore, it has been disclosed that Akt can beactivated by growth signals that are independent of PI3K.

Alternatively, Akt activity can be inhibited by blocking the activity ofthe upstream kinase PDK1. The compound UCN-01 is a reported inhibitor ofPDK1. Biochem. J. 375(2):255 (2003). Again, inhibition of PDK1 wouldresult in inhibition of multiple protein kinases whose activities dependon PDK1, such as atypical PKC isoforms, SGK, and S6 kinases (Williams etal. Curr. Biol. 10:439-448 (2000).

Small molecule inhibitors of Akt are useful in the treatment of tumors,especially those with activated Akt (e.g. PTEN null tumors and tumorswith ras mutations). PTEN is a critical negative regulator of Akt andits function is lost in many cancers, including breast and prostatecarcinomas, glioblastomas, and several cancer syndromes includingBannayan-Zonana syndrome (Maehama, T. et al. Annual Review ofBiochemistry, 70: 247 (2001)), Cowden disease (Parsons, R.; Simpson, L.Methods in Molecular Biology (Totowa, N.J., United States), 222 (TumorSuppressor Genes, Volume 1): 147 (2003)), and Lhermitte-Duclos disease(Backman, S. et al. Current Opinion in Neurobiology, 12(5): 516 (2002)).Akt3 is up-regulated in estrogen receptor-deficient breast cancers andandrogen-independent prostate cancer cell lines and Akt2 isover-expressed in pancreatic and ovarian carcinomas. Akt1 is amplifiedin gastric cancers (Staal, Proc. Natl. Acad. Sci. USA 84: 5034-7 (1987)and upregulated in breast cancers (Stal et al. Breast Cancer Res. 5:R37-R44 (2003)). Therefore a small molecule Akt inhibitor is expected tobe useful for the treatment of these types of cancer as well as othertypes of cancer. Akt inhibitors are also useful in combination withfurther chemotherapeutic and anticancer agents.

It is an object of the instant invention to provide novel compounds thatare inhibitors of Akt/PKB.

It is also an object of the present invention to provide pharmaceuticalcompositions that comprise a pharmaceutical carrier and compounds usefulin the methods of the invention.

It is also an object of the present invention to provide a method fortreating cancer that comprises administering such inhibitors of Akt/PKBactivity.

It is also an object of the present invention to provide a method fortreating arthritis that comprises administering such inhibitors ofAkt/PKB activity.

SUMMARY OF THE INVENTION

This invention relates to novel compounds of Formula (I):

wherein:

-   -   R⁴¹ and R⁴² are independently selected from: hydrogen,

halogen, C₁₋₄alkyl, substituted C₁₋₄alkyl, C₁₋₄alkyloxy, substitutedC₁₋₄alkyloxy, furan, substituted fruan, thiophene and substitutedthiophene,

-   -   where Q and Y are independently selected from: nitrogen and        —C(R⁷⁰)—, and Z is selected from: nitrogen and    -   —C(R⁴⁸)—, provided that at least one and at most 2 of Q, Y and Z        are nitrogen, and R³⁰ is selected from: C₁₋₄alkyl and C₁₋₄alkyl        substituted with form one to three fluorine atoms,    -   where R⁷⁰ is selected from: hydrogen, and halogen, and    -   R⁴⁸ is selected from: hydrogen, C₁₋₄alkyl, substituted        C₁₋₄alkyl, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, cylcoalkyl, substituted cycloalkyl,        heterocycloalkyl, substituted heterocycloalkyl, and halogen;    -   R⁴³ is selected from: hydrogen, halogen, C₁₋₄alkyl, substituted        C₁₋₄alkyl, C₁₋₄alkyloxy, substituted C₁₋₄alkyloxy, furan and        thiophene;    -   R⁴⁴ is absent or selected from: —(CR⁶⁰R⁶¹)_(m)AR wherein the AR        is unsubstituted, —(CR⁶⁰R⁶¹)_(m)AR wherein the AR is substituted        and C₁₋₆alkyl,        -   where m is 0 to 3 and AR is a cyclic or polycyclic aromatic            or saturated or unsaturated non-aromatic ring containing            from 3 to 16 carbon atoms and optionally containing from one            to three heteroatoms, provided that when the ring is            aromatic and the number of carbon atoms is 3 the ring            contains at least two heteroatoms and when the ring is            aromatic and the number of carbon atoms is 4 the ring            contains at least one heteroatom, and R⁶⁰ and R⁶¹ are            independently selected from: hydrogen and C₁₋₄alkyl,            provided that when m is 3 no more than 4 of R⁶⁰ and R⁶¹ when            added together are C₁₋₄alkyl,    -   R⁴⁵ is selected from hydrogen and C₁₋₄alkyl;    -   R²⁰ is selected from hydrogen, C₁₋₄alkyl and hydroxy;    -   X is selected from O, S and NR⁴⁹,        -   where R⁴⁹ is selected from hydrogen and C₁₋₄alkyl; and    -   n is 0 to 2 and this moiety is optionally, if applicable,        substituted by hydroxyC₁₋₄alkyl;

provided that one and only one of R⁴¹ and R⁴² is

and/or pharmaceutically acceptable salts thereof.

This invention relates to a method of treating cancer, which comprisesadministering to a subject in need thereof an effective amount of anAkt/PKB inhibiting compound of Formula (I).

This invention relates to a method of treating arthritis, whichcomprises administering to a subject in need thereof an effective amountof an Akt/PKB inhibiting compound of Formula (I).

The present invention also relates to the discovery that the compoundsof Formula (I) are active as inhibitors of Akt/PKB.

In a further aspect of the invention there is provided novel processesand novel intermediates useful in preparing the presently inventedAkt/PKB inhibiting compounds.

Included in the present invention are pharmaceutical compositions thatcomprise a pharmaceutical carrier and compounds useful in the methods ofthe invention.

Also included in the present invention are methods of co-administeringthe presently invented Akt/PKB inhibiting compounds with further activeingredients.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of Formula (I) as described above.

The presently invented compounds of Formula (I) inhibit Akt/PKBactivity. In particular, the compounds disclosed herein inhibit each ofthe three Akt/PKB isoforms.

Included among the presently invented compounds of Formula (I) are thosein which:

-   -   R⁴¹ and R⁴² are independently selected from: hydrogen,

halogen, C₁₋₄alkyl, substituted C₁₋₄alkyl, C₁₋₄alkyloxy, substitutedC₁₋₄alkyloxy, furan, substituted fruan, thiophene and substitutedthiophene,

-   -   where Q is nitrogen, Y is selected from: nitrogen and —C(R⁷⁰)—,        and Z is selected from: nitrogen and    -   —C(R⁴⁸)—, provided that at most one of Y and Z are nitrogen, and    -   R³⁰ is selected from: C₁₋₄alkyl and C₁₋₄alkyl substituted with        form one to three fluorine atoms,    -   where R⁷⁰ is selected from: hydrogen, and halogen, and    -   R⁴⁸ is selected from: hydrogen, C₁₋₄alkyl, substituted        C₁₋₄alkyl, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, cylcoalkyl, substituted cycloalkyl,        heterocycloalkyl, substituted heterocycloalkyl, and halogen;    -   R⁴³ is selected from: hydrogen, halogen, C₁₋₄alkyl, substituted        C₁₋₄alkyl, C₁₋₄alkyloxy, substituted C₁₋₄alkyloxy, furan and        thiophene;    -   R⁴⁴ is absent or selected from: —(CR⁶⁰R⁶¹)_(m)AR wherein the AR        is unsubstituted, —(CR⁶⁰R⁶¹)_(m)AR wherein the AR is substituted        and C₁₋₆alkyl,        -   where m is 0 to 3 and AR is a cyclic or polycyclic aromatic            or saturated or unsaturated non-aromatic ring containing            from 3 to 16 carbon atoms and optionally containing from one            to three heteroatoms, provided that when the ring is            aromatic and the number of carbon atoms is 3 the ring            contains at least two heteroatoms and when the ring is            aromatic and the number of carbon atoms is 4 the ring            contains at least one heteroatom, and        -   R⁶⁰ and R⁶¹ are independently selected from: hydrogen and            C₁₋₄alkyl, provided that when m is 3 no more than 4 of R⁶⁰            and R⁶¹ when added together are C₁₋₄alkyl,    -   R⁴⁵ is selected from hydrogen and C₁₋₄alkyl;    -   R²⁰ is selected from hydrogen, C₁₋₄alkyl and hydroxy;    -   X is selected from O, S and NR⁴⁹,        -   where R⁴⁹ is selected from hydrogen and C₁₋₄alkyl; and    -   n is 0 to 2 and this moiety is optionally, if applicable,        substituted by hydroxyC₁₋₄alkyl;    -   provided that one and only one of R⁴¹ and R⁴² is

and/or pharmaceutically acceptable salts thereof.

Included among the presently invented compounds of Formula (I) are thosein which:

-   -   R⁴¹ and R⁴² are independently selected from: hydrogen,

halogen, C₁₋₄alkyl, trifluoromethyl, methoxy, furan and thiophene,

-   -   where Q is nitrogen, Y is selected from: nitrogen and —C(R⁷⁰)—,        and Z is selected from: nitrogen and    -   —C(R⁴⁸)—, provided that at most one of Y and Z are nitrogen, and    -   R³⁰ is C₁₋₄alkyl,    -   where R⁷⁰ is selected from: hydrogen, and halogen, and    -   R⁴⁸ is selected from: hydrogen, C₁₋₄alkyl, trifluoromethyl,        aryl, heteroaryl, cylcoalkyl, heterocycloalkyl, and halogen;    -   R⁴³ is selected from: hydrogen, halogen, C₁₋₄alkyl and methoxy;    -   R⁴⁴ is absent or selected from: —(CR⁶⁰R⁶¹)_(m)AAR wherein the        AAR is unsubstituted, —(CR⁶⁰R⁶¹)_(m)AAR wherein the AAR is        substituted and C₁₋₆alkyl,        -   where m is 0 to 3 and AAR is selected from phenyl, indole,            naphthalene, pyridine and cyclohexyl, and        -   R⁶⁰ and R⁶¹ are independently selected from: hydrogen and            methyl, provided that when m is 3 no more than 4 of R⁶⁰ and            R⁶¹ when added together are methyl,    -   R⁴⁵ is selected from hydrogen and C₁₋₄alkyl;    -   R²⁰ is selected from hydrogen, methyl and hydroxy;    -   X is selected from O, S and NR⁴⁹,        -   where R⁴⁹ is selected from hydrogen and methyl; and    -   n is 1 to 2 and this moiety is optionally substituted by        hydroxylmethyl;

provided that one and only one of R⁴¹ and R⁴² is

and/or pharmaceutically acceptable salts thereof.

Included among the presently invented compounds of Formula (I) are thosein which:

-   -   R⁴¹ and R⁴² are independently selected from: hydrogen,

halogen, C₁₋₄alkyl, trifluoromethyl, methoxy and furan,

-   -   where Q is nitrogen, Y is selected from: nitrogen and —C(R⁷⁰)—,        and Z is selected from: nitrogen and    -   —C(R⁴⁸)—, provided that at most one of Y and Z are nitrogen, and    -   R³⁰ is C₁₋₄alkyl,    -   where R⁷⁰ is selected from: hydrogen, and halogen, and    -   R⁴⁸ is selected from: hydrogen, C₁₋₄alkyl, trifluoromethyl,        phenyl, cyclopropyl, and halogen;    -   R⁴³ is selected from: hydrogen, halogen, C₁₋₄alkyl and methoxy;    -   R⁴⁴ is absent or selected from: —(CR⁶⁰R⁶¹)_(m)AAR wherein the        AAR is unsubstituted, —(CR⁶⁰R⁶¹)_(m)AAR wherein the AAR is        substituted and C₁₋₆alkyl,        -   where m is 0 to 3 and AAR is selected from phenyl, indole,            naphthalene, pyridine and cyclohexyl, and        -   R⁶⁰ and R⁶¹ are independently selected from: hydrogen and            methyl, provided that when m is 3 no more than 4 of R⁶⁰ and            R⁶¹ when added together are methyl,    -   R⁴⁵ is selected from hydrogen and C₁₋₄alkyl;    -   R²⁰ is selected from hydrogen, methyl and hydroxy;    -   X is selected from O, S and NR⁴⁹,        -   where R⁴⁹ is selected from hydrogen and methyl; and    -   n is 1 to 2 and this moiety is optionally substituted by        hydroxylmethyl;

provided that one and only one of R⁴¹ and R⁴² is

and/or pharmaceutically acceptable salts thereof.

Included among the presently invented compounds of Formula (I) are thosein which:

-   -   R⁴¹ is selected from: chlorine, ethyl, methyl and methoxy;    -   R⁴² is

-   -   where Q is nitrogen, Y is —CH— and Z is —C(R⁴⁸)—, and    -   R³⁰ is selected from methyl and ethyl,    -   where R⁴⁸ is selected from: hydrogen, methyl, chlorine and        bromine;    -   R⁴³ is hydrogen;    -   R⁴⁴ is —CH₂-phenyl wherein the phenyl is substituted by one or        two substituents selected from fluorine and trifluoromethyl;    -   R⁴⁵ is hydrogen;    -   R²⁰ is hydrogen;    -   X is selected from O and S; and    -   n is 1;        and/or pharmaceutically acceptable salts thereof.

Included in the presently invented compounds of Formula (I) arecompounds of Formula (AA):

wherein:

-   -   R¹ and R² are independently selected from: hydrogen,

halogen, C₁₋₄alkyl, furan and thiophene,

-   -   where R⁶ is C₁₋₄alkyl and R⁷ is selected from hydrogen,        C₁₋₄alkyl and halogen;    -   R³ is selected from: hydrogen, halogen, C₁₋₄alkyl, furan and        thiophene;    -   R⁴ is selected from —(CH₂)_(m)aryl and —(CH₂)_(m)aryl wherein        the aryl is substituted,        -   where m is 0 to 2;    -   R⁵ is selected from hydrogen and C₁₋₄alkyl;    -   X is selected from O and S; and    -   n is 0 to 2;    -   provided that one and only one of R¹ and R² is

and further provided that at least one of R¹, R² and R³ is hydrogen;and/or pharmaceutically acceptable salts thereof.

Included in the presently invented compounds of Formula (I) arecompounds of Formula (BB):

wherein:

-   -   R⁸ and R⁹ are independently selected from: hydrogen, halogen,        C₁₋₄alkyl, furan and thiophene;    -   R⁶ is C₁₋₄alkyl;    -   R⁷ is selected from hydrogen, C₁₋₄alkyl and halogen;    -   R¹⁰ is selected from: —(CH₂)_(m)C₅-C₁₂aryl and        —(CH₂)_(m)C₅-C₁₂aryl wherein the aryl is substituted,        -   where m is 0 to 2;    -   R¹¹ is selected from hydrogen and C₁₋₄alkyl;    -   X is selected from O and S; and    -   provided that at least one of R⁸ and R⁹ is hydrogen;        and/or pharmaceutically acceptable salts thereof.

Included in the presently invented compounds of Formula (I) arecompounds of Formula (CC):

wherein:

-   -   R¹² is selected from: hydrogen, halogen, C₁₋₄alkyl, furan and        thiophene;    -   R¹³ is selected from: —(CH₂)_(m)phenyl and —(CH₂)_(m)phenyl        wherein the phenyl is substituted,        -   where m is 0 to 2;    -   X is selected from O and S; and        and/or pharmaceutically acceptable salts thereof.

Included among the compounds useful in the present invention are:

-   N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-(2-amino-1-phenylethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-{[(2Z)-1-methyl-2-(2-propen-1-ylidene)hydrazino]methyl}-2-thiophenecarboxamide;-   N-(2-amino-1-phenylethyl)-4-{[(2Z)-1-methyl-2-(2-propen-1-ylidene)hydrazino]methyl}-2-thiophenecarboxamide;-   N-(2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-(2-amino-1-phenylethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[3-amino-1-(phenylmethyl)propyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   4-bromo-N-[2-(methylamino)-1-phenylethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[1-(aminomethyl)-3-phenylpropyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[1-(aminomethyl)-3-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   4-bromo-N-[3-(methylamino)-1-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[3-(methylamino)-1-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   4-bromo-N-[2-(methylamino)-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide-   N-((1S)-2-amino-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[1-(aminomethyl)-2-methyl-2-phenylpropyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-(methylamino)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[1-(aminomethyl)-2-methyl-2-phenylpropyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-imidazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2-chlorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(1H-indol-3-ylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(1-naphthalenyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(1-naphthalenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-(3-amino-1-phenylpropyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-N-hydroxy-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,6-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexyl    methyl)ethyl]-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-chloro-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(3-pyridinylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1R)-2-amino-1-phenylethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(4-fluorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(4-chlorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(3-chlorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(2-chlorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(4-fluorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide;-   N-[2-amino-1-(2-chlorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(3-chlorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-(2-aminoethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[2-amino-1-(4-chlorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-phenylethyl]-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-methylethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[3-(trifluoromethyl)phenyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-[(1S)-1-(aminomethyl)-3-methylbutyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   (N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-diethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-[2-amino-1-(phenylmethyl)ethyl]-3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-chloro-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-5-methyl-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-furancarboxamide;-   N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide;-   N-[(1S,2S)-2-amino-3-hydroxy-1-phenylpropyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;-   N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide;    and-   N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide;    and/or pharmaceutically acceptable salts thereof.

Compounds of Formula (I) are included in the pharmaceutical compositionsof the invention and used in the methods of the invention.

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers.Accordingly, the compounds of this invention include mixtures ofenantiomers as well as purified enantiomers or enantiomerically enrichedmixtures. Also, it is understood that all tautomers and mixtures oftautomers are included within the scope of the compounds of Formula (I).

Certain compounds described herein may form a solvate which isunderstood to be a complex of variable stoichiometry formed by a solute(in this invention, a compound of Formula I a salt thereof) and asolvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include, but are not limited to, water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include, without limitation, water,ethanol and acetic acid. Most preferably the solvent used is water.

By the term “aryl”, and derivatives thereof, used alone or as part of alarger moiety as in “—(CH₂)_(m)aryl” as used herein, unless otherwisedefined, is meant monocyclic, bicyclic, and tricyclic ring systemshaving a total of five to fourteen ring members, wherein at least onering system is aromatic and wherein each ring in the system contains 3to 7 members, such as phenyl, naphthalene, tetrahydronaphthalene andbiphenyl.

Suitably, by the term “aryl” is meant a monocyclic aromatic ring systemhaving a total of five to 7 ring members.

By the term “heteroaryl”, and derivatives thereof, used alone or as partof a larger moiety as in “—(CH₂)_(m)heteroaryl” as used herein, unlessotherwise defined, is meant a cyclic aromatic ring containing from 3 to7 carbon atoms and containing from one to 3 heteroatoms, provided thatwhen the number of carbon atoms is 3 the aromatic ring contains at leasttwo heteroatoms. Exemplary “heteroaryl” groups include pyridine andindole.

By the term “cycloalkyl”, and derivatives thereof, used alone or as partof a larger moiety as in “—(CH₂)_(m)cycloalkyl” as used herein, unlessotherwise defined, is meant a non-aromatic cyclic hydrocarbon ringhaving from three to seven carbon atoms. Exemplary “cycloalkyl” groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

By the term “heterocycloalkyl”, and derivatives thereof, used alone oras part of a larger moiety as in “—(CH₂)_(m)heterocycloalkyl” as usedherein, unless otherwise defined, is meant a non-aromatic cyclichydrocarbon ring having from three to six carbon atoms and containing 1or 2 heteroatoms. Exemplary “cycloalkyl” groups include piperazine andpyrrolidine.

By the term “C₅-C₁₂aryl”, used alone or as part of a larger moiety as in“—(CH₂)_(m)C₅-C₁₂aryl”, as used herein, is meant an aromatic groupselected from: phenyl, naphthalene, tehrahydronaphthanlene and biphenyl.

The term “substituted” as used herein, unless otherwise defined, ismeant that the subject chemical moiety has from one to fivesubstituents, suitably from one to three substituents, selected from thegroup consisting of: —CO₂R²⁰, C₁-C₄alkyl, hydroxyC₁-C₄alkyl,C₁-C₄alkyloxy, amino, C₁-C₄alkylamino, aminoC₁-C₄alkyl,diC₁-C₄alkylamino, hydroxy, nitro, tetrazole, cyano, oxo, halogen andtrifluoromethyl, where R²⁰ is selected form hydrogen, C₁-C₄alkyl, andtrifluoromethyl.

Suitably, the term “substituted” as used herein is meant that thesubject chemical moiety has from one to three substituents, selectedfrom the group consisting of: C₁-C₄alkyl, hydroxyC₁-C₄alkyl,C₁-C₄alkyloxy, amino, C₁-C₄alkylamino, aminoC₁-C₄alkyl, hydroxy,tetrazole, halogen and trifluoromethyl.

Suitably, the term “substituted” as used herein is meant that thesubject chemical moiety has from one to three substituents, selectedfrom the group consisting of: halogen and trifluoromethyl.

By the term “heteroatom” as used herein is meant oxygen, nitrogen orsulfur.

By the term “halogen” as used herein is meant a substituent selectedfrom bromide, iodide, chloride and fluoride.

By the term “alkyl” and derivatives thereof and in all carbon chains asused herein, including alkyl chains defined by the term “—(CH₂)_(n)”,“—(CH₂)_(m)” and the like, is meant a linear or branched, saturated orunsaturated hydrocarbon chain, and unless otherwise defined, the carbonchain will contain from 1 to 12 carbon atoms. Examples of alkyl as usedherein include: —CH₃, —CH₂—CH₃, —CH₂—CH₂-CH₃, —CH(CH₃)₂,—CH₂—CH₂-C(CH₃)₃, —C≡C—C(CH₃)₃, —C(CH₃)₃, —(CH₂)₃—CH₃, —CH₂—CH(CH₃)₂,—CH(CH₃)—CH₂—CH₃, —CH═CH₂, and —C≡C—CH₃.

By the term “treating” and derivatives thereof as used herein, is meantprophylactic and therapeutic therapy. Prophylactic therapy isappropriate, for example, when a subject is considered at high risk fordeveloping cancer, or when a subject has been exposed to a carcinogen.

As used herein, the term “effective amount” and derivatives thereofmeans that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” and derivativesthereof means any amount which, as compared to a corresponding subjectwho has not received such amount, results in improved treatment,healing, prevention, or amelioration of a disease, disorder, or sideeffect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function.

Compounds of Formula (I) are included in the pharmaceutical compositionsof the invention and used in the methods of the invention. Where a —COOHor —OH group is present, pharmaceutically acceptable esters can beemployed, for example methyl, ethyl, pivaloyloxymethyl, and the like for—COOH, and acetate maleate and the like for —OH, and those esters knownin the art for modifying solubility or hydrolysis characteristics, foruse as sustained release or prodrug formulations.

The pharmaceutically acceptable salts of the compounds of the inventionare readily prepared by those of skill in the art.

The novel compounds of Formulas (I), (AA), (BB) and (CC) are generallyprepared as shown in Schemes 1 to 3 below, or by analogous methods,provided the X and ‘R’ substituents in Formulas (I), (AA), (BB) and (CC)respectively do not include any such substituents that renderinoperative the processes of any of Schemes 1 to 3. All of the startingmaterials are commercially available or are readily made fromcommercially available starting materials by those of skill in the art.

General Schemes

Amino alcohol (I-1) was reacted under Mitsunobu conditions to providethe differentially protected diamine (I-2). Mitsunobu reactions are wellknow to those skilled in the art of organic synthesis. Methods andreaction conditions for such transformations are discussed in Synthesis1981, 1-28. Selective deprotection of the phthalimide group of (I-2)using a nucleophilic amine such as hydrazine or methyl amine in a polarsolvent such as methanol, afforded amine (I-3). Many differentprotecting groups are available to one skilled in the art and can beused here as long as they do not interfere with the processes listedherein. Methods for the protection of amines are described in standardreference volumes, such as Greene “Protective Groups in OrganicSynthesis” (published by Wiley-Interscience).

Carboxylic acid (II-1) was reacted with 1,1-dimethylethyl(2-amino-3-phenylpropyl)carbamate to form amide (II-2). A variety ofamide coupling reagents such as EDC, PyBrop, etc. are commerciallyavailable. Amide coupling reactions are generally run in solvents suchas DCM or DMF, utilizing an organic base like Et₃N or (i-Pr)₂NEt.Dibromide (II-2) was regioselectively coupled with 1,1-dimethylethyl(2-{[(4,5-dibromo-2-furanyl)carbonyl]amino}-3-phenylpropyl)carbamateusing a Suzuki coupling procedure. Suzuki-like couplings are typicallyrun using a palladium(0) catalyst such as Pd(PPh₃)₄ with an inorganicbase, for example K₂CO₃, Na₂CO₃ or K₃PO₄, in an aqueous mixturecontaining ethereal solvents such as DME, dioxane, or THF. Methods forpalladium-mediated couplings are described in standard referencevolumes, such as Schlosser “Organometallics in Synthesis” (published byWiley and sons). Acidic treatment of II-3 with HCl or TFA to remove theBoc protecting group produced amine (II-4). Many different protectinggroups are available to one skilled in the art and can be used here aslong as they do not interfere with the processes listed herein. Methodsfor the protection of amines are described in standard referencevolumes, such as Greene “Protective Groups in Organic Synthesis”(published by Wiley-Interscience).

Carboxylic acid (III-1) was esterified under standard Fisheresterification conditions and then selectively halogenated with the aidof a Lewis acid to give (III-2). The dihalogenated ester was selectivelycoupled with5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole usingSuzuki coupling chemistry to give (III-3). Suzuki-like couplings aretypically run using a palladium(0) catalyst such as Pd(PPh₃)₄ with aninorganic base, for example K₂CO₃, Na₂CO₃ or K₃PO₄, in an aqueousmixture containing ethereal solvents such as DME, dioxane, or THF.Methods for palladium-mediated couplings are described in standardreference volumes, such as Schlosser “Organometallics in Synthesis”(published by Wiley and sons). Ester (III-3) was chlorinated using NCSand in situ saponified using aqueous NaOH. The resulting carboxylic acid(III-4) was coupled with2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dioneto form amide (III-5). A variety of amide coupling reagents such as EDC,PyBrop, etc. are commercially available. Amide coupling reactions aregenerally run in solvents such as DCM or DMF, utilizing an organic baselike Et₃N or (i-Pr)₂NEt. Amide (III-5) was deprotected using hydrazineto give amine (III-6). Many different protecting groups are available toone skilled in the art and can be used here as long as they do notinterfere with the processes listed herein. Methods for the protectionof amines are described in standard reference volumes, such as Greene“Protective Groups in Organic Synthesis” (published byWiley-Interscience).

By the term “co-administering” and derivatives thereof as used herein ismeant either simultaneous administration or any manner of separatesequential administration of an AKT inhibiting compound, as describedherein, and a further active ingredient or ingredients, known to beuseful in the treatment of cancer, including chemotherapy and radiationtreatment, or to be useful in the treatment of arthritis. The termfurther active ingredient or ingredients, as used herein, includes anycompound or therapeutic agent known to or that demonstrates advantageousproperties when administered to a patient in need of treatment forcancer or arthritis. Preferably, if the administration is notsimultaneous, the compounds are administered in a close time proximityto each other. Furthermore, it does not matter if the compounds areadministered in the same dosage form, e.g. one compound may beadministered topically and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus asusceptible tumor being treated may be co-administered in the treatmentof cancer in the present invention. Examples of such agents can be foundin Cancer Principles and Practice of Oncology by V. T. Devita and S.Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers. A person of ordinary skill in the art would be ableto discern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Typicalanti-neoplastic agents useful in the present invention include, but arenot limited to, anti-microtubule agents such as diterpenoids and vincaalkaloids; platinum coordination complexes; alkylating agents such asnitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclines, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; signal transduction pathway inhibitors;non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeuticagents; proapoptotic agents; and cell cycle signaling inhibitors.

Examples of a further active ingredient or ingredients (anti-neoplasticagent) for use in combination or co-administered with the presentlyinvented AKT inhibiting compounds are chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 50,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. It was first isolated in 1971 by Wani et al. J. Am.Chem., Soc., 93:2325.1971), who characterized its structure by chemicaland X-ray crystallographic methods. One mechanism for its activityrelates to paclitaxel's capacity to bind tubulin, thereby inhibitingcancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA,77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar,J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis andanticancer activity of some paclitaxel derivatives see: D. G. I.Kingston et al., Studies in Organic Chemistry vol. 26, entitled “Newtrends in Natural Products Chemistry 1986”, Attaur-Rahman, P. W. LeQuesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment ofrefractory ovarian cancer in the United States (Markman et al., YaleJournal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann.Intem, Med., 111:273, 1989) and for the treatment of breast cancer(Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potentialcandidate for treatment of neoplasms in the skin (Einzig et. al., Proc.Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastireet. al., Sem. Oncol., 20:56, 1990). The compound also shows potentialfor the treatment of polycystic kidney disease (Woo et. al., Nature,368:750. 1994), lung cancer and malaria. Treatment of patients withpaclitaxel results in bone marrow suppression (multiple cell lineages,Ignoff, R. J. et. al, Cancer Chemotherapy Pocket Guide, 1998) related tothe duration of dosing above a threshold concentration (50 nM) (Kearns,C. M. et. al., Seminars in Oncology, 3(6) p. 16-23, 1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine,N-tert-butyl ester,13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-diacetyl-baccatin III, extracted from the needle of the European Yewtree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine,3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate(1:2)(salt)], commercially available as an injectable solution ofvinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.Vinorelbine is indicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer. The primary dose limiting side effects of cisplatin arenephrotoxicity, which may be controlled by hydration and diuresis, andototoxicity.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)-O,O′],is commercially available as PARAPLATIN® as an injectable solution.Carboplatin is primarily indicated in the first and second linetreatment of advanced ovarian carcinoma. Bone marrow suppression is thedose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea,vomiting and leukopenia are the most common dose limiting side effectsof cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-resectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease. Bone marrow suppression is the most common doselimiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia. Bone marrow suppression is the mostcommon dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commerciallyavailable as single vials of lyophilized material as BiCNU®. Carmustineis indicated for the palliative treatment as a single agent or incombination with other agents for brain tumors, multiple myeloma,Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppressionis the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are themost common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, andanorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma. Myelosuppression is the most common dose limiting side effectof daunorubicin.

Doxorubicin,(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblastic leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas. Myelosuppression is the most common dose limiting side effectof doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneoustoxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Myelosuppression is the most common sideeffect of etoposide. The incidence of leukopenia tends to be more severethan thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.Myelosuppression is the most common dose limiting side effect ofteniposide. Teniposide can induce both leukopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Myelosuppression and mucositis are dose limitingside effects of 5-fluorouracil. Other fluoropyrimidine analogs include5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinemonophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabineinduces leukopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. Myelosuppression and gastrointestinal mucositis are expectedside effects of mercaptopurine at high doses. A useful mercaptopurineanalog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia.Myelosuppression, including leukopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of thioguanine administration.However, gastrointestinal side effects occur and can be dose limiting.Other purine analogs include pentostatin, erythrohydroxynonyladenine,fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride(β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.Myelosuppression, including leukopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of gemcitabine administration.

Methotrexate,N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamicacid, is commercially available as methotrexate sodium. Methotrexateexhibits cell phase effects specifically at S-phase by inhibiting DNAsynthesis, repair and/or replication through the inhibition ofdyhydrofolic acid reductase which is required for synthesis of purinenucleotides and thymidylate. Methotrexate is indicated as a single agentor in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, andcarcinomas of the breast, head, neck, ovary and bladder.Myelosuppression (leukopenia, thrombocytopenia, and anemia) andmucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with itsactive metabolite SN-38, to the topoisomerase I-DNA complex. It isbelieved that cytotoxicity occurs as a result of irreparable doublestrand breaks caused by interaction of the topoisomerase I:DNA:irintecanor SN-38 ternary complex with replication enzymes. Irinotecan isindicated for treatment of metastatic cancer of the colon or rectum. Thedose limiting side effects of irinotecan HCl are myelosuppression,including neutropenia, and GI effects, including diarrhea.

Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dionemonohydrochloride, is commercially available as the injectable solutionHYCAMTIN®. Topotecan is a derivative of camptothecin which binds to thetopoisomerase I-DNA complex and prevents religation of singles strandbreaks caused by Topoisomerase I in response to torsional strain of theDNA molecule. Topotecan is indicated for second line treatment ofmetastatic carcinoma of the ovary and small cell lung cancer. The doselimiting side effect of topotecan HCl is myelosuppression, primarilyneutropenia.

Also of interest, is the camptothecin derivative of formula A following,currently under development, including the racemic mixture (R,S) form aswell as the R and S enantiomers:

known by the chemical name“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptothecin(racemic mixture) or “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R)-camptothecin (Renantiomer) or“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin(S enantiomer). Such compound as well as related compounds aredescribed, including methods of making, in U.S. Pat. Nos. 6,063,923;5,342,947; 5,559,235; 5,491,237 and pending U.S. patent application Ser.No. 08/977,217 filed Nov. 24, 1997.

Hormones and hormonal analogues are useful compounds for treatingcancers in which there is a relationship between the hormone(s) andgrowth and/or lack of growth of the cancer. Examples of hormones andhormonal analogues useful in cancer treatment include, but are notlimited to, adrenocorticosteroids such as prednisone and prednisolonewhich are useful in the treatment of malignant lymphoma and acuteleukemia in children; aminoglutethimide and other aromatase inhibitorssuch as anastrozole, letrazole, vorazole, and exemestane useful in thetreatment of adrenocortical carcinoma and hormone dependent breastcarcinoma containing estrogen receptors; progestrins such as megestrolacetate useful in the treatment of hormone dependent breast cancer andendometrial carcinoma; estrogens, androgens, and anti-androgens such asflutamide, nilutamide, bicalutamide, cyproterone acetate and5α-reductases such as finasteride and dutasteride, useful in thetreatment of prostatic carcinoma and benign prostatic hypertrophy;anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene,iodoxyfene, as well as selective estrogen receptor modulators (SERMS)such those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and6,207,716, useful in the treatment of hormone dependent breast carcinomaand other susceptible cancers; and gonadotropin-releasing hormone (GnRH)and analogues thereof which stimulate the release of leutinizing hormone(LH) and/or follicle stimulating hormone (FSH) for the treatmentprostatic carcinoma, for instance, LHRH agonists and antagonists such asgoserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation. Signaltransduction inhibitors useful in the present invention includeinhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,SH2/SH3domain blockers, serine/threonine kinases, phosphatidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation ofspecific tyrosyl residues in various proteins involved in the regulationof cell growth. Such protein tyrosine kinases can be broadly classifiedas receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having anextracellular ligand binding domain, a transmembrane domain, and atyrosine kinase domain. Receptor tyrosine kinases are involved in theregulation of cell growth and are generally termed growth factorreceptors. Inappropriate or uncontrolled activation of many of thesekinases, i.e. aberrant kinase growth factor receptor activity, forexample by over-expression or mutation, has been shown to result inuncontrolled cell growth. Accordingly, the aberrant activity of suchkinases has been linked to malignant tissue growth. Consequently,inhibitors of such kinases could provide cancer treatment methods.Growth factor receptors include, for example, epidermal growth factorreceptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2,erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosinekinase with immunoglobulin-like and epidermal growth factor homologydomains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophagecolony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growthfactor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin(eph) receptors, and the RET protooncogene. Several inhibitors of growthreceptors are under development and include ligand antagonists,antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.Growth factor receptors and agents that inhibit growth factor receptorfunction are described, for instance, in Kath, John C., Exp. Opin. Ther.Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 Feb. 1997;and Lofts, F. J. et al, “Growth factor receptors as targets”, NewMolecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr,David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases aretermed non-receptor tyrosine kinases. Non-receptor tyrosine kinases foruse in the present invention, which are targets or potential targets ofanti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focaladhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Suchnon-receptor kinases and agents which inhibit non-receptor tyrosinekinase function are described in Sinh, S. and Corey, S. J., (1999)Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; andBolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15:371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domainbinding in a variety of enzymes or adaptor proteins including, PI3-K p85subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) andRas-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussedin Smithgall, T. E. (1995), Journal of Pharmacological and ToxicologicalMethods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascadeblockers which include blockers of Raf kinases (rafk), Mitogen orExtracellular Regulated Kinase (MEKs), and Extracellular RegulatedKinases (ERKs); and Protein kinase C family member blockers includingblockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase familymembers, and TGF beta receptor kinases. Such Serine/Threonine kinasesand inhibitors thereof are described in Yamamoto, T., Taya, S.,Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt,P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology,60.1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.27:41-64; Philip, P. A., and Harris, A. L. (1995), Cancer Treatment andResearch. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal ChemistryLetters, (10), 2000, 223-226; U.S. Pat. No. 6,268,391; andMartinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

Inhibitors of Phosphatidyl inositol-3 Kinase family members includingblockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in thepresent invention. Such kinases are discussed in Abraham, R. T. (1996),Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S.(1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), InternationalJournal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. etal, Cancer res, (2000) 60(6), 1541-1545.

Also of interest in the present invention are Myo-inositol signalinginhibitors such as phospholipase C blockers and Myoinositol analogues.Such signal inhibitors are described in Powis, G., and Kozikowski A.,(1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workmanand David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitorsof Ras Oncogene. Such inhibitors include inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases aswell as anti-sense oligonucleotides, ribozymes and immunotherapy. Suchinhibitors have been shown to block ras activation in cells containingwild type mutant ras, thereby acting as antiproliferation agents. Rasoncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R.,Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7(4)292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99-102;and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligandbinding may also serve as signal transduction inhibitors. This group ofsignal transduction pathway inhibitors includes the use of humanizedantibodies to the extracellular ligand binding domain of receptortyrosine kinases. For example Imclone C225 EGFR specific antibody (seeGreen, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, CancerTreat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (seeTyrosine Kinase Signalling in Breast cancer:erbB Family ReceptorTyrosine Kinases, Breast Cancer Res., 2000, 2(3), 176-183); and 2CBVEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibitionof VEGFR2Activity by a monoclonal Anti-VEGF antibody blocks tumor growthin mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors may also be useful in thepresent invention. Inhibitors of angiogenesis related VEGFR and TIE2 arediscussed above in regard to signal transduction inhibitors (bothreceptors are receptor tyrosine kinases). Angiogenesis in general islinked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR havebeen shown to inhibit angiogenesis, primarily VEGF expression.Accordingly, non-receptor tyrosine kinase inhibitors may be used incombination with the compounds of the present invention. For example,anti-VEGF antibodies, which do not recognize VEGFR (the receptortyrosine kinase), but bind to the ligand; small molecule inhibitors ofintegrin (alpha_(v) beta₃) that will inhibit angiogenesis; endostatinand angiostatin (non-RTK) may also prove useful in combination with thedisclosed compounds. (See Bruns C J et al (2000), Cancer Res., 60:2926-2935; Schreiber A B, Winkler M E, and Derynck R. (1986), Science,232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

Agents used in immunotherapeutic regimens may also be useful incombination with the compounds of formula (I). There are a number ofimmunologic strategies to generate an immune response. These strategiesare generally in the realm of tumor vaccinations. The efficacy ofimmunologic approaches may be greatly enhanced through combinedinhibition of signaling pathways using a small molecule inhibitor.Discussion of the immunologic/tumor vaccine approach against erbB2/EGFRare found in Reilly R T et al. (2000), Cancer Res. 60: 3569-3576; andChen Y, Hu D, Eling D J, Robbins J, and Kipps T J. (1998), Cancer Res.58: 1965-1971.

Agents used in proapoptotic regimens (e.g., bcl-2 antisenseoligonucleotides) may also be used in the combination of the presentinvention. Members of the Bcl-2 family of proteins block apoptosis.Upregulation of bcl-2 has therefore been linked to chemoresistance.Studies have shown that the epidermal growth factor (EGF) stimulatesanti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore,strategies designed to downregulate the expression of bcl-2 in tumorshave demonstrated clinical benefit and are now in Phase II/III trials,namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptoticstrategies using the antisense oligonucleotide strategy for bcl-2 arediscussed in Water J S et al. (2000), J. Clin. Oncol. 18: 1812-1823; andKitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Cell cycle signalling inhibitors inhibit molecules involved in thecontrol of the cell cycle. A family of protein kinases called cyclindependent kinases (CDKs) and their interaction with a family of proteinstermed cyclins controls progression through the eukaryotic cell cycle.The coordinate activation and inactivation of different cyclin/CDKcomplexes is necessary for normal progression through the cell cycle.Several inhibitors of cell cycle signalling are under development. Forinstance, examples of cyclin dependent kinases, including CDK2, CDK4,and CDK6 and inhibitors for the same are described in, for instance,Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.

In one embodiment, the cancer treatment method of the claimed inventionincludes the co-administration a compound of Formula (I) and/or apharmaceutically acceptable salt thereof and at least oneanti-neoplastic agent, such as one selected from the group consisting ofanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,and cell cycle signaling inhibitors.

Because the pharmaceutically active compounds of the present inventionare active as AKT inhibitors they exhibit therapeutic utility intreating cancer and arthritis.

Suitably, the present invention relates to a method for treating orlessening the severity of a cancer selected from: brain (gliomas),glioblastomas, Bannayan-Zonana syndrome, Cowden disease,Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm'stumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma,colon, head and neck, kidney, lung, liver, melanoma, ovarian,pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone,thyroid,

Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chroniclymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia, Chronic neutrophilic leukemia, Acutelymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cellleukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblasticleukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocyticleukemia, Erythroleukemia,

malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,

neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvalcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer.

Suitably, the present invention relates to a method for treating orlessening the severity of a cancer selected from: brain (gliomas),glioblastomas, Bannayan-Zonana syndrome, Cowden disease,Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung,liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

Suitably, the present invention relates to a method for treating orlessening the severity of a cancer selected from ovarian, breast,pancreatic and prostate.

Isolation and Purification of His-Tagged AKT1 (aa 136-480)

Insect cells expressing His-tagged AKT1 (aa 136-480) were lysed in 25 mMHEPES, 100 mM NaCl, 20 mM imidazole; pH 7.5 using a polytron (5 mLslysis buffer/g cells). Cell debris was removed by centrifuging at28,000×g for 30 minutes. The supernatant was filtered through a4.5-micron filter then loaded onto a nickel-chelating columnpre-equilibrated with lysis buffer. The column was washed with 5 columnvolumes (CV) of lysis buffer then with 5 CV of 20% buffer B, wherebuffer B is 25 mM HEPES, 100 mM NaCl, 300 mM imidazole; pH 7.5.His-tagged AKT1 (aa 136-480) was eluted with a 20-100% linear gradientof buffer B over 10 CV. His-tagged AKT1 (136-480) eluting fractions werepooled and diluted 3-fold with buffer C, where buffer C is 25 mM HEPES,pH 7.5. The sample was then chromatographed over a Q-Sepharose HP columnpre-equilibrated with buffer C. The column was washed with 5 CV ofbuffer C then step eluted with 5 CV 10% D, 5 CV 20% D, 5 CV 30% D, 5 CV50% D and 5 CV of 100% D; where buffer D is 25 mM HEPES, 1000 mM NaCl;pH 7.5. His-tagged AKT1 (aa 136-480) containing fractions were pooledand concentrated in a 10-kDa molecular weight cutoff concentrator.His-tagged AKT1 (aa 136-480) was chromatographed over a Superdex 75 gelfiltration column pre-equilibrated with 25 mM HEPES, 200 mM NaCl, 1 mMDTT; pH 7.5. His-tagged AKT1 (aa 136-480) fractions were examined usingSDS-PAGE and mass spec. The protein was pooled, concentrated and frozenat −80 C.

His-tagged AKT2 (aa 138-481) and His-tagged AKT3 (aa 135-479) wereisolated and purified in a similar fashion.

His-Tagged AKT Enzyme Assay

Compounds of the present invention were tested for AKT 1, 2, and 3protein serine kinase inhibitory activity in substrate phosphorylationassays. This assay examines the ability of small molecule organiccompounds to inhibit the serine phosphorylation of a peptide substrate.The substrate phosphorylation assays use the catalytic domains of AKT 1,2, or 3. AKT 1, 2 and 3 are also commercially available from UpstateUSA, Inc. The method measures the ability of the isolated enzyme tocatalyze the transfer of the gamma-phosphate from ATP onto the serineresidue of a biotinylated synthetic peptide SEQ. ID NO: 1(Biotin-ahx-ARKRERAYSFGHHA-amide). Substrate phosphorylation wasdetected by the following procedure:

Assays were performed in 384well U-bottom white plates. 10 nM activatedAKT enzyme was incubated for 40 minutes at room temperature in an assayvolume of 20 ul containing 50 mM MOPS, pH 7.5, 20 mM MgCl₂, 4 uM ATP, 8uM peptide, 0.04 uCi [g-³³P] ATP/well, 1 mM CHAPS, 2 mM DTT, and 1 ul oftest compound in 100% DMSO. The reaction was stopped by the addition of50 ul SPA bead mix (Dulbecco's PBS without Mg²⁺ and Ca²⁺, 0.1% TritonX-100, 5 mM EDTA, 50 uM ATP, 2.5 mg/ml Streptavidin-coated SPA beads.)The plate was sealed, the beads were allowed to settle overnight, andthen the plate was counted in a Packard Topcount MicroplateScintillation Counter (Packard Instrument Co., Meriden, Conn.).

The data for dose responses were plotted as % Control calculated withthe data reduction formula 100*(U1−C2)/(C1−C2) versus concentration ofcompound where U is the unknown value, C1 is the average control valueobtained for DMSO, and C2 is the average control value obtained for 0.1MEDTA. Data are fitted to the curve described by: y=((Vmax*x)/(K+x))where Vmax is the upper asymptote and K is the IC50.

Cloning of Full-Length Human (FL) AKT1:

Full-length human AKT1 gene was amplified by PCR from a plasmidcontaining myristylated-AKT1-ER (gift from Robert T. Abraham, DukeUniversity under MTA, described in Klippel et al. in Molecular andCellular Biology 1998 Volume 18 p. 5699) using the 5′ primer: SEQ. IDNO: 2, 5′ TATATAGGATCCATGAGCGACGTGGC 3′ and the 3′ primer: SEQ. ID NO:3, AAATTTCTCGAGTCAGGCCGTGCTGCTGG 3′. The 5′ primer included a BamHI siteand the 3′primer included an XhoI site for cloning purposes. Theresultant PCR product was subcloned in pcDNA3 as a BamHI/XhoI fragment.A mutation in the sequence (IGC) coding for a Cysteine²⁵ was convertedto the wild-type AKT1 sequence (CGC) coding for an Arginine²⁵ bysite-directed mutagenesis using the QuikChange® Site DirectedMutagenesis Kit (Stratagene). The AKT1 mutagenic primer: SEQ. ID NO:4,5′ ACCTGGCGGCCACGCTACTTCCTCC and selection primer: SEQ. ID NO: 5,5′CTCGAGCATGCAACTAGAGGGCC (designed to destroy an XbaI site in themultiple cloning site of pcDNA3) were used according to manufacturer'ssuggestions. For expression/purification purposes, AKT1 was isolated asa BamHI/XhoI fragment and cloned into the BamHI/XhoI sites ofpFastbacHTb (Invitrogen).

Expression of FL Human AKT1:

Expression was done using the BAC-to-BAC Baculovirus Expression Systemfrom Invitrogen (catalog #10359-016). Briefly 1) the cDNA wastransferred from the FastBac vector into bacmid DNA, 2) the bacmid DNAwas isolated and used to transfect Sf9 insect cells, 3) the virus wasproduced in Sf9 cells, 4) T. ni cells were infected with this virus andsent for purification.

Purification of FL Human AKT1:

For the purification of full-length AKT1, 130 g sf9 cells (batch #41646W02) were resuspended in lysis buffer (buffer A, 1 L, pH 7.5)containing 25 mM HEPES, 100 mM NaCl, and 20 mM imidazole. The cell lysiswas carried out by Avestin (2 passes at 15K-20K psi). Cell debris wasremoved by centrifuging at 16K rpm for 1 hour and the supernatant wasbatch bound to 10 ml Nickel Sepharose HP beads at 4 C for over night.The beads were then transferred to column and the bound material waseluted with buffer B (25 mM HEPES, 100 mM NaCl, 300 mM imidazole, pH7.5). AKT eluting fractions were pooled and diluted 3 fold using bufferC (25 mM HEPES, 5 mM DTT; pH 7.5). The sample was filtered andchromatographed over a 10 mL Q-HP column pre-equilibrated with buffer Cat 2 mL/min.

The Q-HP column was washed with 3 column volume (CV) of buffer C, thenstep eluted with 5 CV 10% D, 5 CV 20% D, 5 CV 30% D, 5 CV 50% D and 5 CVof 100% D; where buffer D is 25 mM HEPES, 1000 mM NaCl, 5 mM DTT; pH7.5. 5 mL fractions collected. AKT containing fractions were pooled andconcentrated to 5 ml. The protein was next loaded to a 120 ml Superdex75 sizing column that was pre-equilibrated with 25 mM HEPES, 200 mMNaCl, 5 mM DTT; pH 7.5. 2.5 mL fractions were collected.

AKT 1 eluting fractions were pooled, aliquoted (1 ml) and stored at −80C. Mass spec and SDS-PAGE analysis were used to confirm purity andidentity of the purified full-length AKT1.

Full length AKT2 and full length AKT3 were cloned, expressed andpurified in a similar fashion.

AKT Enzyme Assay

Compounds of the present invention are tested for AKT 1, 2, and 3protein serine kinase inhibitory activity in substrate phosphorylationassays. This assay examines the ability of small molecule organiccompounds to inhibit the serine phosphorylation of a peptide substrate.The substrate phosphorylation assays use the catalytic domains of AKT 1,2, or 3. AKT 1, 2 and 3 are also commercially available from UpstateUSA, Inc. The method measures the ability of the isolated enzyme tocatalyze the transfer of the gamma-phosphate from ATP onto the serineresidue of a biotinylated synthetic peptide SEQ. ID NO: 1(Biotin-ahx-ARKRERAYSFGHHA-amide). Substrate phosphorylation is detectedby the following procedure:

Assays are performed in 384well U-bottom white plates. 10 nM activatedAKT enzyme is incubated for 40 minutes at room temperature in an assayvolume of 20 ul containing 50 mM MOPS, pH 7.5, 20 mM MgCl₂, 4 uM ATP, 8uM peptide, 0.04 uCi [g-³³P] ATP/well, 1 mM CHAPS, 2 mM DTT, and 1 ul oftest compound in 100% DMSO. The reaction is stopped by the addition of50 ul SPA bead mix (Dulbecco's PBS without Mg²⁺ and Ca²⁺, 0.1% TritonX-100, 5 mM EDTA, 50 uM ATP, 2.5 mg/ml Streptavidin-coated SPA beads.)The plate is sealed, the beads are allowed to settle overnight, and thenthe plate is counted in a Packard Topcount Microplate ScintillationCounter (Packard Instrument Co., Meriden, Conn.).

The data for dose responses are plotted as % Control calculated with thedata reduction formula 100*(U1−C2)/(C1−C2) versus concentration ofcompound where U is the unknown value, C1 is the average control valueobtained for DMSO, and C2 is the average control value obtained for 0.1MEDTA. Data are fitted to the curve described by: y=((Vmax*x)/(K+x))where Vmax is the upper asymptote and K is the IC50.

Compounds of the invention are tested for activity against AKT1, AKT2,and AKT3 in one or more of the above assays.

The majority of the compounds of the Examples were tested generallyaccording to the above AKT enzyme assays and in at least oneexperimental run exhibited a plC50 value: ≧5.9 against full length AKT1;≧5.0 against full length AKT2; and ≧5.0 against full length AKT3.

The compounds of Examples 31, 32, 91, 95, 120, 128, 140, 161, 167, 169,170, 190, 222, 225, 237, 249, 258 and 259 were tested generallyaccording to the above AKT enzyme assays and in at least oneexperimental run exhibited a plC50 value: ≧8.6 against full length AKT1;and ≧7.5 against full length AKT2. The majority of the compounds ofExamples 31, 32, 91, 95, 120, 128, 140, 161, 167, 169, 170, 190, 222,225, 237, 249, 258 and 259 were tested generally according to the aboveAKT enzyme assays and in at least one experimental run exhibited a plC50value; ≧7.6 against full length AKT3.

The compound of Example 96 was tested generally according to the aboveAKT enzyme assays and in at least one experimental run exhibited a plC50value: equal to 9.0 against full length AKT1; equal to 8.0 against fulllength AKT2; and equal to 8.8 against full length AKT3.

The compound of Example 137 was tested generally according to the aboveAKT enzyme assays and in at least one experimental run exhibited a plC50value: equal to 9.0 against full length AKT1; equal to 7.8 against fulllength AKT2; and equal to 8.4 against full length AKT3.

The compound of Example 224 was tested generally according to the aboveAKT enzyme assays and in at least one experimental run exhibited a plC50value: equal to 8.7 against full length AKT1; and equal to 7.8 againstfull length AKT2.

The compound of Example 161 was tested generally according to the aboveAKT enzyme assays and in at least one experimental run exhibited a plC50value: equal to 8.8 against full length AKT1; equal to 7.5 against fulllength AKT2; and equal to 7.6 against full length AKT3.

The compound of Example 222 was tested generally according to the aboveAKT enzyme assays and in at least one experimental run exhibited a plC50value: equal to 8.8 against full length AKT1; and equal to 7.9 againstfull length AKT2; and equal to 8.5 against full length AKT3.

In the above data, plC50 is defined as −log(IC50) where the IC50 valueis expressed in molar units.

The pharmaceutically active compounds within the scope of this inventionare useful as AKT inhibitors in mammals, particularly humans, in needthereof.

The present invention therefore provides a method of treating cancer,arthritis and other conditions requiring AKT inhibition, which comprisesadministering an effective compound of Formula (I) and/or apharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof.The compounds of Formula (I) also provide for a method of treating theabove indicated disease states because of their demonstrated ability toact as Akt inhibitors. The drug may be administered to a patient in needthereof by any conventional route of administration, including, but notlimited to, intravenous, intramuscular, oral, subcutaneous, intradermal,and parenteral.

The pharmaceutically active compounds of the present invention areincorporated into convenient dosage forms such as capsules, tablets, orinjectable preparations. Solid or liquid pharmaceutical carriers areemployed. Solid carriers include, starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, and stearic acid. Liquid carriers include syrup,peanut oil, olive oil, saline, and water. Similarly, the carrier ordiluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount ofsolid carrier varies widely but, preferably, will be from about 25 mg toabout 1 g per dosage unit. When a liquid carrier is used, thepreparation will be in the form of a syrup, elixir, emulsion, softgelatin capsule, sterile injectable liquid such as an ampoule, or anaqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating,and compressing, when necessary, for tablet forms, or mixing, fillingand dissolving the ingredients, as appropriate, to give the desired oralor parenteral products.

Doses of the presently invented pharmaceutically active compounds in apharmaceutical dosage unit as described above will be an efficacious,nontoxic quantity preferably selected from the range of 0.001-100 mg/kgof active compound, preferably 0.001-50 mg/kg. When treating a humanpatient in need of an Akt inhibitor, the selected dose is administeredpreferably from 1-6 times daily, orally or parenterally. Preferred formsof parenteral administration include topically, rectally, transdermally,by injection and continuously by infusion. Oral dosage units for humanadministration preferably contain from 0.05 to 3500 mg of activecompound. Oral administration, which uses lower dosages, is preferred.Parenteral administration, at high dosages, however, also can be usedwhen safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular Akt inhibitor inuse, the strength of the preparation, the mode of administration, andthe advancement of the disease condition. Additional factors dependingon the particular patient being treated will result in a need to adjustdosages, including patient age, weight, diet, and time ofadministration.

The method of this invention of inducing Akt inhibitory activity inmammals, including humans, comprises administering to a subject in needof such activity an effective Akt inhibiting amount of apharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) inthe manufacture of a medicament for use as an Akt inhibitor.

The invention also provides for the use of a compound of Formula (I) inthe manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I) inthe manufacture of a medicament for use in treating cancer.

The invention also provides for the use of a compound of Formula (I) inthe manufacture of a medicament for use in treating arthritis.

The invention also provides for a pharmaceutical composition for use asan Akt inhibitor which comprises a compound of Formula (I) and apharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use inthe treatment of cancer which comprises a compound of Formula (I) and apharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use intreating arthritis which comprises a compound of Formula (I) and apharmaceutically acceptable carrier.

No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the present invention.

In addition, the pharmaceutically active compounds of the presentinvention can be co-administered with further active ingredients, suchas other compounds known to treat cancer or arthritis, or compoundsknown to have utility when used in combination with an Akt inhibitor.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples are, therefore, to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way.

Experimental Details

The compounds of Examples 1 to 328 are readily made according to Schemes1 to 3 or by analogous methods.

Preparation 1 Preparation of 1,1-dimethylethyl(2-amino-2-phenylethyl)carbamate

a) 1,1-dimethylethyl (2-hydroxy-2-phenylethyl)carbamate

To a solution of 2-amino-1-phenylethanol (5 g, 36.4 mmol) in THF (182mL) at 25° C. was added Boc₂O (8.7 g, 40.1 mmol) in one portion. After0.5 h, the solution was concentrated and the residue used directlywithout further purification: LC-MS (ES) m/z=238 (M+H)⁺.

b)1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate

To a solution of 1,1-dimethylethyl (2-hydroxy-2-phenylethyl)carbamate (2g, 8.44 mmol), phthalimide (1 g, 7.03 mmol) and triphenylphosphine (2.76g, 10.5 mmol) in THF (35 mL) at 25° C. was added DEAD (1.7 mL, 10.5mmol) dropwise. After 0.5 h, the solution was concentrated and purifiedvia column chromatography (silica, 15% EtOAc in hexanes) affording thetitle compound (2 g, 80%) as a white foam: LC-MS (ES) m/z=367 (M+H)⁺.

c) 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate

A solution of1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate(2 g, 5.46 mmol) and either MeNH₂ (40 wt % in H₂O, 10 eq.) or NH₂NH₂ (10eq.) in MeOH (0.5M, 10 mL) was heated to 60° C. in a sealed tube. After12 h, the solution was concentrated and purified via columnchromatography (silica-dry load, 2% MeOH in DCM (1% NH₄OH)) affordingthe title compound (1.1 g, 85%) as a white solid: LC-MS (ES) m/z=237(M+H)⁺.

Preparation 2

Preparation of 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate a)1-amino-3-phenyl-2-propanol

A solution of 2-(phenylmethyl)oxirane (7.5 g, 56.3 mmol) in NH₄OH (100mL) was stirred at 25° C. in a sealed tube. After 12 h, the solution wasconcentrated and used directly: LCMS (ES) m/e 152 (M+H)⁺.

b) 1,1-dimethyl ethyl (2-hydroxy-3-phenylpropyl)carbamate

To a solution of 1-amino-3-phenyl-2-propanol (7.6 g, 50 mmole) in THF(50 mL) at RT was added (Boc)₂O (12.0 g, 55 mmole). After stirring at RTfor 2 h, the reaction solution was concentrated under vacuum and theresidue purified on silica gel (5% MeOH in DCM (0.5% NH₄OH)) affordingthe title compound (13.1 g, 91%) as a clear yellow oil: LCMS (ES) m/z252 (M+H)⁺.

c)1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl)carbamate(10.0 g, 39.8 mmol), PPh₃ (12.5 g, 47.8 mmol) and phthalimide (6.44 g,43.8 mmol) in THF (125 mL) at RT was added DEAD (9.4 mL, 59.7 mmol) over5 min. After 1 h at RT, the reaction solution was concentrated andpurified on silica (hexanes/EtOAc, 2:1) to give the title compound as awhite solid (12.6 g, 83%): LCMS (ES) m/z 381 (M+H)⁺.

d) 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate

NH₂NH₂ (12.5 mL, 394 mmol) was added to a THF/MeOH (50 mL/50 mL)solution of 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate (7.5 g,19.7 mmol) and stirred at 50° C. in a sealed system. After 12 hours, thesolids were filtered, washing with methanol. The filtrate wasconcentrated and purified by column chromatography using 5% MeOH inCHCl₃ containing 0.5% NH₄OH to give the title compound (3.75 g, 76%) asa white solid: LC-MS (ES) m/z=251 (M+H)⁺.

Preparation 3

Preparation of 1,1-dimethylethyl (3-amino-3-phenylpropyl)carbamate a)3-amino-1-phenyl-1-propanol

Benzoylacetonitrile (2 g, 13.8 mmol) in THF (35 mL) was added dropwisevia addition funnel to a 0° C. solution of LAH (1.6 g, 41.3 mmol) in THF(35 mL). The resulting solution warmed to 25° C. and then was heated to60° C. for an additional 2 h. After cooling to 0° C., a saturatedsolution of sodium potassium tartrate was added dropwise and thesolution was extracted several times with DCM. The combined organicfractions were dried (Na₂SO₄), concentrated and purified via columnchromatography (silica, 5-8% MeOH in DCM (1% NH₄OH)) affording the aminoalcohol (1.4 g, 67%) as a clear oil: LCMS (ES) m/z 152 (M+H)⁺.

b) 1,1-dimethyl ethyl (3-hydroxy-3-phenylpropyl)carbamate

3-amino-1-phenyl-1-propanol (1.4 g, 9.27 mmol) was dissolved in THF (50mL) and Boc₂O (2.4 g, 11.1 mmol) was added in one portion. After 30min., the solution was concentrated and the residue purified through viasilica (0.5-1% MeOH in DCM (1% NH₄OH)) affording the title compound (1.6g, 69%) as a pale white solid: LCMS (ES) m/z 152 (M+H)⁺.

c)1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl (3-hydroxy-3-phenylpropyl)carbamate(3 g, 11.95 mmol), PPh₃ (4 g, 15.5 mmol) and phthalimide (1.8 g, 11.95mmol) in THF (60 mL) at RT was added DEAD (2.4 mL, 15.5 mmol) over 5min. After 1 h at RT, the reaction solution was concentrated andpurified on silica (hexanes/EtOAc, 4:1) to give the title compound as awhite solid (2.2 g, 48%): LCMS (ES) m/z 381 (M+H)⁺.

c) 1,1-dimethylethyl (3-amino-3-phenylpropyl)carbamate

NH₂NH₂ (1.8 mL, 57.7 mmol) was added to a THF/MeOH (1:1, 30 mL) solutionof1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate(2.2 g, 5.79 mmol) and stirred at 50° C. in a sealed system. After 12hours, the solids were filtered, washing with methanol. The filtrate wasconcentrated and purified by column chromatography using 5% MeOH inCHCl₃ containing 1% NH₄OH to give the title compound (1.1 g, 76%) as awhite solid: LC-MS (ES) m/z=251 (M+H)⁺.

Preparation 4

Preparation of 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate a)2-(2-phenylethyl)oxirane

3-chlorobenzenecarboperoxoic acid (12.1 g, 54.0 mmol) is added in oneportion to a solution of 3-buten-1-ylbenzene (7.15 g, 54.1 mmol) inCH₂Cl₂ at 0° C. followed by warming to 25° C. overnight. SaturatedNaHCO₃ was added and the mixture separated and the resulting clear oil(8.0 g, quant.) was carried forward without further purification: LC-MS(ES) m/z=149 (M+H)⁺.

b) 1-amino-4-phenyl-2-butanol

2-(2-phenylethyl)oxirane (8.0 g, 54 mmol) was placed in a sealed tubewith 7N NH₃-MeOH (130 mL) and stirred 2 hours at 70° C. followed byconcentration to a clear oil (and was used without further purificationin the following step.

c) 1,1-dimethylethyl (2-hydroxy-4-phenylbutyl)carbamate

1-amino-4-phenyl-2-butanol (7.4 g, 50.0 mmol) was dissolved in THF (50mL) and Boc₂O (13 g, 59.6 mmol) was added in one portion. After 30 min.,the solution was concentrated and the residue purified through a silicaplug (5% MeOH in DCM (0.5% NH₄OH)) affording the title compound (13.1 g,91%) as a clear yellow oil: LCMS (ES) m/z 266 (M+H)⁺.

d)1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-phenylbutyl]carbamate

To a solution of 1,1-dimethylethyl (2-hydroxy-4-phenylbutyl)carbamate(3.0 g, 11.4 mmol), PPh₃ (3.6 g, 13.7 mmol) and phthalimide (1.84 g,12.5 mmol) in THF (60 mL) at RT was added DEAD (1.8 mL, 11.4 mmol) over5 min. After 0.5 h at RT, the reaction solution was concentrated andpurified on silica (hexanes/EtOAC, 2:1) to give the title compound as awhite solid (3.1 g, 69%): LCMS (ES) m/z 395 (M+H)⁺.

e) 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate

NH₂NH₂ (2.5 mL, 79.6 mmol) was added to a THF/MeOH (40 mL/40 mL)solution of 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate (3.1 g,7.83 mmol) and stirred overnight. After 12 hours, the solution wasconcentrated and purified by column chromatography using 5% MeOH inCHCl₃ containing 0.5% NH₄OH to give the title compound (1.4 g, 66%) as awhite solid: LC-MS (ES) m/z=265 (M+H)⁺.

Preparation 5

Preparation of2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione a)1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]carbamate

To a solution of(S)-(−)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (3.0 g, 11.9mmole), PPh₃ (3.74 g, 14.4 mmole) and phthalimide (1.93 g, 13.1 mmole)in THF (75 mL) at RT was added DEAD (2.8 mL, 17.8 mmole) over 5 min.After 1.5 h at RT, the reaction solution was concentrated and purifiedon silica (hexanes/EtOAC, 2:1) to give the title compound as a whitesolid (4.3 g, 95%): LCMS (ES) m/z 381 (M+H)⁺.

b) 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione

To a solution of1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]carbamate(4.3 g, 11.3 mmole) in MeOH (100 mL) at RT was added 4M HCl in dioxane(50 mL). After stirring for 3 h at RT, the reaction solution wasconcentrated to a white solid (quant.): LCMS (ES) m/z 281 (M+H)⁺.

Preparation 6

Preparation of2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dionea) 1,1-dimethylethyl((1S)-2-hydroxy-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate

To a solution ofN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine(5 g, 15 mmol) in THF (75 mL) at 0° C. stirred was added BH₃-THF (45 mL,45 mmol-1M in THF). After 12 h, the reaction was quenched with AcOH:MeOH(1:5, 24 mL) and partitioned between saturated aqueous NaHCO₃ and DCM.The aqueous phase was then extracted several times with DCM. Thecombined organic fractions were dried over Na₂SO₄ and used directly (4.2g, 88%): LCMS (ES) m/e 320 (M+H)⁺.

b) 1,1-dimethylethyl((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate

To a solution of 1,1-dimethylethyl((1S)-2-hydroxy-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate(4.2 g, 13.2 mmol), triphenylphosphine (4.5 g, 17.1 mmol) andphthalimide (1.9 g, 13.2 mmol) in THF (66 mL) at 25° C. was addeddiethyl azodicarboxylate (2.7 mL, 17.1 mmol). After stirring at RT for 1h, the reaction solution was concentrated under vacuum and the residuepurified on silica gel (1% MeOH in DCM) affording the title compound(3.2 g, 54%) as a white solid: LCMS (ES) m/z 449 (M+H)⁺.

c)2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione

To a solution of 1,1-dimethylethyl((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate(3.2 g, 7.1 mmol) in MeOH (35 mL) at RT was added 4M HCl in dioxane (18mL). After 12 h, the solution was concentrated affording the titlecompound (2.7 g, quant.) as the HCl salt: LCMS (ES) m/z 349 (M+H)⁺.

Preparation 7

Preparation of5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole

To a solution of 1-methylpyrazole (4.1 g, 50 mmole) in THF (100 mL) at0° C. was added n-BuLi (2.2M in THF, 55 mmole). The reaction solutionwas stirred for 1 hour at RT and then cooled to −78° C. [J. HeterocyclicChem. 41, 931 (2004)]. To the reaction solution was added2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.3 mL, 60mmole). After 15 min at −78° C., the reaction was allowed to warm to 0°C. over 1 hour. The reaction was diluted with saturated NH₄Cl solutionand extracted with DCM. The organic fractions were washed with H₂O(2×100 mL), dried over Na₂SO₄ and concentrated under vacuum to afford atan solid (8.0 g, 77%) which was used without further purification. LCMS(ES) m/z 127 (M+H)⁺ for [RB(OH)₂]; ¹H NMR (CDCl₃, 400 MHz) δ 7.57 (s,1H), 6.75 (s, 1H), 4.16 (s, 3H), and 1.41 (s, 12H).

Preparation 8

Preparation of 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate a)3-oxo-4-phenylbutanenitrile

To a solution of cyanoacetic acid (2 g, 23.5 mmol) in THF (100 mL) at−78° C. was added nBuLi (10 mL, 25.9 mmol, 2.5M in hexanes). After 30min, phenylacetyl chloride (1.6 mL, 11.8 mmol) was added dropwise.Following an additional 30 min, the solution was partitioned between 1NHCl-Et₂O and the aqueous phase was washed several times with Et₂O. Thecombined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (silica, 30% EtOAc in hexanes)yielding the title compound (770 mg, 40%) as a tan oil: LCMS (ES) m/z160 (M+H)⁺.

b) 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate

A solution of 3-oxo-4-phenylbutanenitrile (1.1 g, 6.92 mmol) in THF (10mL) was added to a 0° C. solution of lithium aluminum hydride (787 mg,20.8 mmol) in THF (25 mL). After 12 h, the solution was quenched withH₂O (943 uL), 6N NaOH (716 uL) and H₂O (3.5 mL). The resultingprecipitate was filtered and the pad was washed several times with DCM.The filtrate was concentrated then redissolved in THF (30 mL) and Boc₂O(1.5 g, 6.92 mmol) was added in one portion. After 30 min, the solutionwas concentrated and purified via column chromatography (silica, 3% MeOHin DCM (1% NH₄OH)) yielding the title compound (1 g, 55%-2steps) as anorange solid: LCMS (ES) m/z 265 (M+H)⁺.

c)1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-phenylbutyl]carbamate

To a solution of 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate (1g, 3.77 mmol), PPh₃ (1.3 g, 4.91 mmol) and phthalimide (555 mg, 3.77mmol) in THF (18 mL) at RT was added DEAD (772 uL, 4.91 mmol) over 5min. After 1 h at RT, the reaction solution was concentrated andpurified on silica (hexanes/EtOAc, 5:1) to give the title compound as awhite solid (725 mg, 49%): LCMS (ES) m/z 395 (M+H)⁺.

d) 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate

NH₂NH₂ (577 uL, 18.4 mmol) was added to a THF/MeOH (1:1, 10 mL) solutionof1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-phenylbutyl]carbamate(725 mg, 1.84 mmol) and stirred at 50° C. in a sealed system. After 12hours, the solids were filtered, washing with methanol. The filtrate wasconcentrated and purified by column chromatography using 5% MeOH inCHCl₃ containing 1% NH₄OH to give the title compound (483 mg, quant.) asa white solid: LC-MS (ES) m/z=264 (M+H)⁺.

Preparation 9

Preparation of 4-bromo-5-methyl-2-thiophenecarboxylic Acid

A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 mL) was addeddropwise to 5-methyl-2-thiophenecarboxylic acid (2 g, 14.1 mmol) andFeCl₃ (456 mg, 2.81 mmol) in AcOH (28 mL) at 25° C. After 5 h, thesolution was poured onto ice and the precipitate was filtered and washedwith water affording the title compound (3 g, quant.) as a yellowpowder: LCMS (ES) m/z 222 (M+H)⁺.

Preparation 10

Preparation of methyl 4-bromo-5-methyl-2-thiophenecarboxylate

A solution of 4-bromo-5-methyl-2-thiophenecarboxylic acid (3 g, 13.6mmol) in MeOH (67 mL) and H₂SO₄ (3 mL) was stirred at 50° C. After 12 h,the solution was added to ice-H₂O and the pH was adjusted to ˜11. Theaqueous phase was extracted several times with DCM and the combinedorganic fractions were dried over Na₂SO₄, concentrated and used directlyyielding the title compound (3 g, 94%) as an orange solid: LCMS (ES) m/z236 (M+H)⁺.

Preparation 11

Preparation of 4-bromo-5-chloro-2-thiophenecarboxylic Acid

A solution of bromine (634 uL, 12.3 mmol) in AcOH (2.5 mL) was addeddropwise to 5-chloro-2-thiophenecarboxylic acid (2 g, 12.3 mmol) andFeCl₃ (399 mg, 2.50 mmol) in AcOH (25 mL) at 25° C. The reaction mixturewas warmed to reflux where additional bromine (634 uL, 12.3 mmol) andFeCl₃ (399 mg, 2.50 mmol) were added. After 7 d, the solution was pouredonto ice and the precipitate was filtered and washed with wateraffording the title compound (3 g, quant.) as a yellow powder: LCMS (ES)m/z 242 (M+H)⁺.

Preparation 12

Preparation of 1,1-dimethylethyl (3-amino-3-phenylpropyl)methylcarbamatea) 1,1-dimethylethyl (3-hydroxy-3-phenylpropyl)methylcarbamate

3-(methylamino)-1-phenyl-1-propanol (4.12 g, 24.9 mmol) was dissolved inTHF (30 mL) and Boc₂O (1M/THF, 30 mL, 30 mmol) was added in one portion.After 30 min., the solution was concentrated and the residue purifiedthrough a silica plug (5% MeOH in DCM (0.5% NH₄OH)) affording the titlecompound (6.4 g, 97%) as a clear yellow oil: LCMS (ES) m/z 265 (M+H)⁺.

b)1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate

To a solution of 1,1-dimethylethyl(3-hydroxy-3-phenylpropyl)methylcarbamate (2.8 g, 10.4 mmol), PPh₃ (3.3g, 12.7 mmol) and phthalimide (1.86 g, 12.6 mmol) in THF (50 mL) at RTwas added DEAD (1.98 mL, 12.6 mmol) over 5 min. After 0.5 h at RT, MeOH(10 mL) was added and the reaction solution was absorbed onto silica andpurified via chromatography (hexanes/EtOAC, 2:1) to give the titlecompound as a white solid (2.7 g, 65%): LCMS (ES) m/z 395 (M+H)⁺.

c) 1,1-dimethylethyl (3-amino-3-phenylpropyl)methylcarbamate

NH₂NH₂ (1.7 mL, 54.2 mmol) was added to a THF/MeOH (50 mL/10 mL)solution of1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate(2.7 g, 6.8 mmol) and stirred overnight. After 12 hours, the solutionwas absorbed onto silica and purified by column chromatography using 5%MeOH in CHCl₃ containing 0.5% NH₄OH to give the title compound (1.4 mg,77%) as a white solid: LC-MS (ES) m/z=265 (M+H)⁺.

Preparation 13

Preparation of 1,1-dimethylethyl (2-amino-3-phenylpropyl)methylcarbamatea) 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl)methylcarbamate

To a solution of 1-(methylamino)-3-phenyl-2-propanol (13 g, 78 mmol)[prepared according to Galons, H. et al Eur. J. Med. Chem. Chim. Ther.1979 14, 165-170.] in THF (390 mL) at RT was added (Boc)₂O (21.6 g, 99mmol). After stirring at RT for 2 h, the reaction solution was absorbedonto silica and purified via chromatography (35% EtOAc/Hex) affordingthe title compound (11.6 g, 56%) as a clear yellow oil: LCMS (ES) m/z266 (M+H)⁺.

b)1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate

To a solution of 1,1-dimethylethyl(2-hydroxy-3-phenylpropyl)methylcarbamate (11.6 g, 43.72 mmol), PPh₃(14.3 g, 54.5 mmol) and phthalimide (8.7 g, 59.1 mmol) in THF (220 mL)at RT was added DEAD (8.5 mL, 54 mmol) over 15 min. After 0.5 h at RT,MeOH (10 mL) was added and the reaction solution was absorbed ontosilica and purified via chromatography (hexanes/EtOAC, 2:1) to give thetitle compound as a white solid (9.97 g, 57%): LCMS (ES) m/z 395 (M+H)⁺.

c) 1,1-dimethylethyl (2-amino-3-phenylpropyl)methylcarbamate

NH₂NH₂ (7 mL, 0.2 mol) was added to a THF/MeOH (100 mL/25 mL) solutionof1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate(2.7 g, 6.8 mmol) and stirred overnight. After 12 hours, the solutionwas absorbed onto silica and purified by column chromatography using 5%MeOH in CHCl₃ containing 0.5% NH₄OH to give the title compound (5.8 mg,88%) as a white solid: LC-MS (ES) m/z=265 (M+H)⁺.

Preparation 14

Preparation of2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione a) methyl2-azido-3-methyl-3-phenylbutanoate

To a solution of KHMDS (36 mL, 17.9 mmol) in THF (70 mL) at −78° C. wasadded methyl 3-methyl-3-phenylbutanoate (3 g, 15.6 mmol) in THF (15 mL)dropwise. After 1 h, trisylazide (5 g, 18.7 mmol) in THF (15 mL) wasadded dropwise over 10 min. After an additional 5 min, acetic acid (4.1mL) was added and the reaction mixture warmed to 25° C. over 1 h. Thesolution was then partitioned between H₂O-DCM and the aqueous phase waswashed several times with DCM. The combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, 20% EtOAc in hexanes) yielding the title compound (2.6 g, 71%)contaminated with 33% methyl 3-methyl-3-phenylbutanoate to be purifiedout in the following steps: LCMS (ES) m/e 234 (M+H)⁺.

b) methyl beta,beta-dimethylphenylalaninate

A solution of methyl 2-azido-3-methyl-3-phenylbutanoate (2.6 g, 11.2mmol) and PPh₃ (4.4 g, 16.7 mmol) in H₂O (400 uL) and THF (100 mL) wasstirred at 25° C. over 2 d then at 50° C. for 12 h. The solution wasconcentrated and purified via column chromatography (silica, 5% MeOH inDCM (1% NH₄OH)) yielding the title compound (1.4 g, quant.): LCMS (ES)m/e 208 (M+H)⁺.

c) 2-amino-3-methyl-3-phenyl-1-butanol

To a solution of methyl beta,beta-dimethylphenylalaninate (1.4 g, 6.76mmol) in THF (20 mL) at 0° C. was added dropwise a solution of lithiumaluminum hydride (384 mg, 10.1 mmol) in THF (10 mL). After warming to25° C. over 12 h, the solution was quenched by sequential addition ofH₂O (659 uL), 6N NaOH (500 uL) and H₂O (2.4 mL). The resultingprecipitate was filtered and the pad washed thoroughly with DCM. Thefiltrate was concentrated and purified via column chromatography(silica, 2-5% MeOH in DCM (1% NH₄OH)) yielding the title compound (770mg, 64%): LCMS (ES) m/e 179 (M+H)⁺.

d) 1,1-dimethylethyl[1-(hydroxymethyl)-2-methyl-2-phenylpropyl]carbamate

Boc₂O (1 g, 4.76 mmol) was added in one portion to2-amino-3-methyl-3-phenyl-1-butanol (770 mg, 4.33 mmol) in THF (20 mL)at 25° C. After 30 min, the solution was concentrated yielding the titlecompound (1.2 g, quant.) as a white solid which was used without furtherpurification: LCMS (ES) m/e 279 (M+H)⁺.

e) 1,1-dimethylethyl{1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-methyl-2-phenylpropyl}carbamate

To a solution of1,1-dimethylethyl[1-(hydroxymethyl)-2-methyl-2-phenylpropyl]carbamate(775 mg, 2.8 mmol), triphenylphosphine (915 mg, 3.5 mmol) andphthalimide (499 mg, 3.4 mmol) in THF (15 mL) at 25° C. was addeddiethyl azodicarboxylate (0.54 mL, 3.4 mmol). After stirring at RT for 1h, MeOH was added (5 mL) and the solution was adsorbed onto silica andpurified via column chromatography (1% MeOH in DCM) affording the titlecompound (723 mg, 64%) as a white solid: LCMS (ES) m/z 409 (M+H)⁺.

f) 2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione

To a solution of 1,1-dimethylethyl{1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-methyl-2-phenylpropyl}carbamate(723 mg, 1.77 mmol) in CHCl₃:MeOH (10:1, 55 mL) at RT was added 4M HClin dioxane (10 mL). After stirring for 3 h at RT, the reaction solutionwas concentrated to a white solid (quant.): LCMS (ES) m/z 309 (M+H)⁺.

Preparation 15

Preparation of 5-iodo-1-methyl-1H-1,2,4-triazole

1-methyl-1H-1,2,4-triazole (2.05 g, 24.7 mmol) was added slowly over 15minutes to an Et₂O solution of nBuLi at −70° C. The mixture was stirredfor 60 minutes at −70° C. and allowed to warm to −30° C. A solution of12 (6.5 g, 25.6 mmol) in THF (27 mL) was added slowly over 15 minutesand the mixture was allowed to warm to room temperature and stir for 60minutes. The mixture was partitioned with saturated Na₂S₂O₃, the phaseswere separated and the organic solvent removed. The crude iodide wasused without further purification: LCMS (ES) m/z 210 (M+H)⁺.

Preparation 16

Preparation of1,1-dimethylethyl[2-amino-2-(1-naphthalenyl)ethyl]carbamate a)hydroxy(1-naphthalenyl)acetonitrile

To a solution of potassium cyanide in ether (100 mL) at 0° C. was addeddropwise a mixture of 1-naphthalenecarbaldehyde (1.56 g, 10 mmol) andacetic acid (1.41 g, 23.5 mmol) in ether (10 mL). The resulting mixturewas warmed to 25° C. for 20 h, where the precipitate was filtered andthe filtrate was concentrated affording the title compound as a clearoil (1.67 g, 9.14 mmol, 91%): LCMS (ES) m/z 184 (M+H)⁺.

b) 2-amino-1-(1-naphthalenyl)ethanol

To a solution of hydroxy(1-naphthalenyl)acetonitrile (1.67 g, 9.14 mol)in THF (90 mL) at 0° C. was added dropwise a solution of LAH-THF (1M, 11mL, 11 mmol). After 2 hrs, the solution was quenched by sequentialaddition of H₂O (0.42 mL), 6N NaOH (6M, 0.32 mL) and H₂O (1.6 mL). Theresulting precipitate was filtered and the filtrate was concentrated andused directly yielding the title compound (0.897 g, 4.8 mmol, 53%) as aclear oil: LCMS (ES) m/z 188 (M+H)⁺.

c). 1,1-dimethylethyl[2-hydroxy-2-(1-naphthalenyl)ethyl]carbamate

To a solution of 2-amino-1-(1-naphthalenyl)ethanol (1.38 g, 4.8 mmol) indichloromethane (50 mL) was added Boc anhydride (1.155 g, 5.3 mmole).After stirring at RT for 12 h, the reaction solution was concentratedand partitioned between NaHCO₃ sat./DCM. The aqueous phase was washedseveral times with DCM. The combined organic fractions were dried overNa₂SO₄, concentrated and used directly yielding the title compound as awhite solid (1.378 g, 4.8 mmol, quant): LCMS (ES) m/z 288 (M+H)⁺.

d)1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-(1-naphthalenyl)ethyl]carbamate

To a solution of1,1-dimethylethyl[2-hydroxy-2-(1-naphthalenyl)ethyl]carbamate (1.38 g,4.8 mmol), triphenylphosphine (1.52 g, 5.76 mmol) and phthalimide (0.74g, 5.04 mmol) in THF (50 mL) at 25° C. was added diethylazodicarboxylate (0.87 mL, 5.52 mmol). After stirring at RT for 1 h, thereaction solution was concentrated under vacuum and the residue purifiedon silica gel (20% EtOAc in hexanes) affording the title compound (1.29g, 3.1 mmol, 65%) as a white solid: LCMS (ES) m/z 387 (M+H)+.

e) 1,1-dimethylethyl[2-amino-2-(1-naphthalenyl)ethyl]carbamate

To a solution of1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-(1-naphthalenyl)ethyl]carbamate(1.29 g, 3.1 mmol) in MeOH (30 mL) was added anhydrous hydrazine (0.5mL, 15.5 mmol) at 25° C. After 12 h, the solution was partitionedbetween DCM/H₂O. The aqueous phase was washed several times with DCM andthe combined organic fractions were dried over Na₂SO₄, concentrated andused directly yielding the title compound as a white solid (491 mg, 1.72mmole, 55%): LCMS (ES) m/z 287 (M+H)⁺.

Preparation 17

Preparation of1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a suspension of NaH (60% in mineral oil, 3.5 g, 146 mmol, washed with200 mL of hexane) in THF (200 mL) was added 4-methyl-1H-pyrazole (10 g,122 mmol) at 0° C. dropwise. After stirring at RT for 1 h, to abovesuspension was added MeI (7.3 mL, 117 mmol) dropwise at 0° C. Thereaction mixture was stirred overnight. The NaI by-product was removedby filtration and the filtrate solution was used directly in the nextstep.

At 0° C., to above THF solution of 1,4-dimethylpyrazole was added n-BuLi(2.5M in hexane, 58.5 mL, 146 mmole). The reaction solution was stirredfor 2 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41,931 (2004)]. To the reaction solution was added2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.2 g, 146mmole). After 15 min at −78° C., the reaction was allowed to warm to 0°C. and stir for 3 h. The reaction was diluted with saturated NH₄Clsolution and extracted with DCM. The organics were dried over Na₂SO₄ andconcentrated under vacuum to afford the title compound as a brown solid(21 g, 78%) which was used directly without further purification: LC-MS:141 (M-C₆H₁₂)⁺, 223 (M+H)⁺. ¹H NMR (CDCl₃): δ 7.28 (s, 1H), 4.03 (s,3H), 2.22 (s, 3H), and 1.32 (s, 12H).

Preparation 18

Preparation of2-[(2S)-2-amino-3-(2,6-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dionea) N-{[(1,1-dimethylethyl)oxy]carbonyl}-2,6-difluoro-L-phenylalanine

1,4-Dioxane (55 mL) and water (12 mL) was added to2,6-difluoro-L-phenylalanine (3.00 g, 12.62 mmol) in a 200 mLround-bottomed flask. The mixture was cooled to 0° C. followed by theslow addition of NaOH (12.62 mL, 31.6 mmol) and then Boc₂O (3.42 g,15.20 mmol). The mixture was allowed to warm to room temperature andmonitored for completion by LC-MS. Upon completion, the mixture wascooled to 0° C. and made neutral by the slow addition of 2.5M HCl (12mL). The solvents removed under reduced pressure. The resulting solidwas sonicated with 20% MeOH/CHCl₃ (150 mL), filtered and the organicsolvent removed to give the product (4.3 g, 14.4 mmol, quant.) as awhite solid which was used in the next step without furtherpurification: LC-MS (ES) m/z=302 (M+H)⁺.

b)1,1-dimethylethyl[(1S)-2-(2,6-difluorophenyl)-1-(hydroxymethyl)ethyl]carbamate

BH₃.THF (64.7 ml, 64.7 mmol) was added slowly to a tetrahydrofuran (THF)(60 mL) solution ofN-{[(1,1-dimethylethyl)oxy]carbonyl}-2,6-difluoro-L-phenylalanine (4.33g, 14.37 mmol) at 0° C. in a 200 mL round-bottomed flask. The mixturewas stirred for 2 hours and then placed in the freezer overnight. Excessreagent was quenched by the slow addition of AcOH in MeOH at 0° C. andthe mixture warmed to room temperature for 2 hours. The THF volume wasreduced by ½ and the product partitioned between CHCl₃ and aqueousNaHCO_(3(sat)). The combined organic fractions were dried over Na₂SO₄and used directly without further purification (3.4 g, 78%): LC-MS (ES)m/z=288 (M+H)⁺.

c) 1,1-dimethylethyl{(1S)-2-(2,6-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate

To a 200 mL round-bottomed flask was added1,1-dimethylethyl[(1S)-2-(2,6-difluorophenyl)-1-(hydroxymethyl)ethyl]carbamate(3.38 g, 11.76 mmol), phthalimide (2.02 g, 13.73 mmol), and PS-TPP(Polymer bound TriphenylPhosphine (2.15 mmol/g, 4.92 g, 14.76 mmol) inTetrahydrofuran (THF) (58.8 ml). DEAD (2.23 ml, 14.09 mmol) was addedand the mixture stirred at ambient temperature for approximately 30minutes at which point MeOH was added. The mixture was filtered throughCelite adsorbed onto silica and purified via column chromatographyaffording the title compound (2.7 g, 55%): LC-MS (ES) m/z=317 (M+H)⁺.

d)2-[(2S)-2-amino-3-(2,6-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione

In a 200 mL round-bottomed flask was added 1,1-dimethylethyl{(1S)-2-(2,6-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate(2.72 g, 6.40 mmol) in Chloroform (75 ml) and Methanol (10 ml).HCl/1,4-Dioxane (40.0 ml, 160 mmol) was added and the mixture stirredovernight. The solvents were removed affording the title compound (2.4g, quant.) as the HCl salt: LC-MS (ES) m/z=317 (M+H)⁺.

Preparation 19

Preparation of2-[(2S)-2-amino-3-(3-pyridinyl)propyl]-1H-isoindole-1,3(2H)-dione a)1,1-dimethylethyl[(1S)-2-hydroxy-1-(3-pyridinylmethyl)ethyl]carbamate

To a solution of Boc-L-3-pyridylaniline (1.064 g, 4 mmol) in THF (5 mL)at 0° C. was added BH₃-THF (20 mL, 20 mmol-1M in THF) dropwise. After 2h, the reaction was quenched with AcOH:MeOH (1:5, 14.3 mL) at 0° C.,followed by Et₃N (1.67 mL, 12 mmol) and 12 (2.03 g, 8 mmol). Theresulting mixture was warmed to ambient temperature and stirred for 20h, turning from brown to colorless. The solution was concentrated andpartitioned between DCM and water. The aqueous phase was then extractedseveral times with DCM. The combined organic fractions were dried overNa₂SO₄ and concentrated to afford the desired product as a colorless oilwhich was used without further purification (957.6 mg, 95%): LC-MS (ES)m/z=253 (M+H)⁺.

b)1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(3-pyridinylmethyl)ethyl]carbamate

To a solution of1,1-dimethylethyl[(1S)-2-hydroxy-1-(3-pyridinylmethyl)ethyl]carbamate(958 mg, 3.8 mmol), triphenylphosphine (1.21 g, 4.6 mmol) andphthalimide (617 mg, 4.2 mmol) in THF (40 mL) at 25° C. was addeddiethyl azodicarboxylate (0.72 mL, 4.6 mmol). After stirring at RT for 1h, the reaction solution was concentrated under vacuum and the residuepurified on silica gel (0-50% ethyl acetate/hexane) affording the titlecompound (797 mg, 55%) as a white solid: LCMS (ES) m/z 382 (M+H)⁺.

c) 2-[(2S)-2-amino-3-(3-pyridinyl)propyl]-1H-isoindole-1,3(2H)-dione

To a solution of1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(3-pyridinylmethyl)ethyl]carbamate(796.7 mg, 2.1 mmol) in DCM (10 mL) at RT was added 1M HCl in dioxane(10 mL). After 20 h, the solution was concentrated affording the titlecompound (404 mg, 68%) as the HCl salt: LCMS (ES) m/z 282 (M+H)⁺.

Preparation 20

Preparation of 1-methyl-1H-1,2,3-triazole

To a solution of 1,2,3-triazole (10 g, 145 mmol) in 150 ml of THF wereadded potassium carbonate (40 g, 290 mmol) and MeI (13.58 ml, 217 mmol).The resulting reaction mixture was stirred at rt for 3 hr. The reactionmixture was filtered and the filtrate was concentrated to afford thetitle compound (9.2 g, 78%). 1H NMR (400 MHz, CDCl₃)

ppm 7.71 (s, 1H), 7.55 (s, 1H), 4.14 (s, 3H).

Preparation 21 Preparation of1,4-dimethyl-5-(tributylstannanyl)-1H-1,2,3-triazole

a) 1,4-dimethyl-1H-1,2,3-triazole

A solution of methylamine (25.4 ml, 50.8 mmol, 2M in MeOH) was addeddropwise to a suspension ofN′-(2,2-dichloro-1-methylethylidene)-4-methylbenzenesulfonohydrazide(ref: Sakai, K. et al, Bull. Chem. Soc. Jpn., 1986, 59, 179-183) (3 g,10.16 mmol) in methanol (10 ml) at 0° C. The solid went into solution.The resulting dark brown mixture was stirred at 0° C. for 2 h,evaporated, and the solid was filtered and rinsed with EtOAc. Thecombined filtrates were concentrated and purified on a 25M biotagecolumn, which was eluted with 50-75% of EA/hexane to give 0.57 g ofbrown liquid. LC-MS (ES) m/z=98 (M+H)⁺, ¹H NMR (CDCl₃, 400 MHz) δ 7.27(s, 1H), 4.06 (s, 3H), 2.35 (s, 3H).

b) 1,4-dimethyl-5-(tributylstannanyl)-1H-1,2,3-triazole

A solution of 1,4-dimethyl-1,2,3-triazole (0.56 g, 5.77 mmol) in THF (5mL) was added dropwise to a solution of BuLi (2.77 ml, 6.92 mmol, 2.5 Min hexane) in 30 mL of THF at −78° C. under N₂. The resulting cloudymixture was stirred at −70° C. for 1 h.

Then tributyltinchloride (1.711 ml, 6.34 mmol) was added. The reactionmixture became clear and was stirred at this temperature for 30 min, andgradually warmed to rt. To the reaction mixture was added 10 ml of NH₄Cland 10 ml of water. The reaction mixture was extracted with ether. Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified on FCC (20% EA/Hexane) to give1.7 g of a clear liquid (73%). LC-MS (ES) m/z=388 (M+H)⁺, ¹H NMR (CDCl₃,400 MHz) δ 4.05 (s, 3H), 2.38 (s, 3H), 1.5-0.9 (m, 27H)

Preparation 22

Preparation of1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(2,4-dichlorophenyl)propyl]carbamate

A solution of 4-bromo-2-thiophenecarboxylic acid (1.29 g, 6.22 mmol),2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(2.0 g, 5.19 mmol), PyBrop (3.62 g, 7.78 mmol) and Hunig's Base (3.62ml, 20.74 mmol) in DCM (50 ml) was stirred at RT for 30 min. Thereaction mixture was washed with H₂O, 1N HCl, NaHCO₃ (sat. aq.) andbrine. The solvent was removed and the residue was dissolved in MeOH,hydrazine monohydrate (1.3 g, 26 mmol) was added. The reaction wasstirred at rt overnight. The white solid formed, and was filtered andrinsed with DCM. To the filtrates were added (Boc)₂O (1.7 g, 7.78 mmol)and NaHCO₃ (sat. aq., 3 ml). The reaction mixture was stirred at RT for2 hours and was washed with NaHCO₃ (sat. aq.) and brine. The solvent wasremoved and the residue was purified by biotage (50% H/E) to give theproduct (2.0 g, 76%). LC-MS (ES) m/z=531.0 (M+Na)⁺.

Example 1

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamidea) 1,1-dimethylethyl(2-{[(4,5-dibromo-2-furanyl)carbonyl]amino}-3-phenylpropyl)carbamate

To a solution of 4,5-dibromo-2-furancarboxylic acid (2.81 g, 10.4 mmol),PyBrOP (5.6 g, 12.0 mmol) and diisopropylethyl amine (4.2 mL, 24.0 mmol)in DCM (70 mL) at 25° C. was added 1,1-dimethylethyl(2-amino-3-phenylpropyl)carbamate (2.0 g, 8.0 mmol). After 16 h, thesolution was partitioned between H₂O and washed with DCM. The combinedorganic fractions were dried (Na₂SO₄), concentrated and purified viacolumn chromatography (silica, hexanes/EtOAc, 2:1) affording the titlecompound (4.3 g, 82%) as a white solid: LC-MS (ES) m/z=503 (M+H)⁺.

b)1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl(2-{[(4,5-dibromo-2-furanyl)carbonyl]amino}-3-phenylpropyl)carbamate(0.30 g, 0.60 mmol) in dioxane/H₂O (5:1, 8.6 mL) was added K₂CO₃ (0.25g, 1.8 mmol), tetrakistriphenylphosphine Pd(0) (70 mg, 0.06 mmol), and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (0.12 g,0.60 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 12 h. The reaction solution was poured onto H₂O (100 mL) andextracted with DCM. The organics were dried (Na₂SO₄), concentrated undervacuum, and purified on silica gel (hexanes/EtOAc, 1:1) to give thetitle compound (0.20 g, 66%) as a white solid: LC-MS (ES) m/z=504.

c)N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

1,1-Dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate(0.20 g, 0.40 mmol) was dissolved in DCM (10 mL) and treated with TFA (5mL). After 2 h, the solution was concentrated, and purified onreverse-phase HPLC (C18 column: H₂O/CH₃CN, 95-5%) affording the TFA saltof the title compound (0.16 g, 91%) as a white powder: LC-MS (ES)m/z=405 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 7.59 (s, 1H), 7.33 (m, 3H),7.30 (m, 2H), 6.85 (s, 1H), 4.57 (m, 1H), 4.03 (s, 3H), 3.25 (m, 1H),3.14 (m, 1H), and 2.98 (m, 2H).

Example 2

Preparation ofN-(2-amino-1-phenylethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 1,1-dimethylethyl(2-{[(5-bromo-2-thienyl)carbonyl]amino}-2-phenylethyl)carbamate

To a solution of 5-bromo-2-thiophenecarboxylic acid (3.2 g, 15.2 mmol),PyBrOP (8.5 g, 18.2 mmol) and diisopropylethyl amine (10.6 mL, 60.9mmol) in DCM (76 mL) at 25° C. was added 1,1-dimethylethyl(2-amino-2-phenylethyl)carbamate (3.6 g, 3.14 mmol)[prepared inPreparation 1]. After 16 h, the solution was partitioned between H₂O andwashed with DCM. The combined organic fraction were dried (Na₂SO₄),concentrated and purified via column chromatography (silica, 1% MeOH inDCM) affording the title compound (4 g, 62%) as a white solid: LC-MS(ES) m/z=426 (M+H)⁺.

b)1,1-dimethylethyl[2-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)ethyl]carbamate

To a solution of 1,1-dimethylethyl(2-{[(5-bromo-2-thienyl)carbonyl]amino}-2-phenylethyl)carbamate (1 g,2.35 mmol) in DMF (9 mL) were added KOAc (693 mg, 7.05 mmol),bis(pinacolato)diboron (1.2 g, 4.71 mmol) and Pd(dppf)Cl₂ (169 mg, 0.212mmol). The reaction contents were heated to 80° C. in a sealed tube for18 hours and were then partitioned between 6N NaOH and DCM. The pH ofthe aqueous fraction was adjusted to ˜3 with 3M HCl and washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated to a solid under vacuum and used directly in the nextreaction: LC-MS (ES) m/z=473 (M+H)⁺ boronic ester, 391 (M+H)⁺ boronicacid.

c)1,1-dimethylethyl[2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate

To a solution of1,1-dimethylethyl[2-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)ethyl]carbamate(200 mg, 0.42 mmol) in dioxane/H₂O (5:1, 8.6 mL) was added K₂CO₃ (234mg, 1.69 mmol), tetrakistriphenylphosphine Pd(0) (24 mg, 0.02 mmol), and5-iodo-1-methyl-1H-pyrazole (97 mg, 0.47 mmol) [prepared according toEffenberger, F.; et al J. Org. Chem. 1984, 49, 24, 4687]. The reactionmixture was heated to 80° C. in a sealed tube for 12 h. The reactionsolution was poured onto H₂O (100 mL) and extracted with DCM. Theorganics were dried (Na₂SO₄), concentrated under vacuum, and purified onsilica gel (1% MeOH in DCM) to give the title compound (56 mg, 31%) as ayellow solid: LC-MS (ES) m/z=427.

d)N-(2-amino-1-phenylethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl[2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate(56 mg, 0.131 mmol) was dissolved in MeOH (2 mL) and treated with excess4M HCl in dioxane (656 μL, 2.62 mmol). After 4 h, the solution wasconcentrated affording the title compound (46 mg, quant.) as a yellowsolid: LC-MS (ES) m/z 327 (M+H)⁺, ¹H NMR (d6-DMSO, 400 MHz) δ 9.46 (d,J=8.2 Hz, 1H), 8.27 (bs, 1H), 8.20 (d, J=4.0 Hz, 1H), 7.48-7.75 (m, 3H),7.37-7.40 (m, 2H), 7.31-7.33 (m, 1H), 6.58 (d, J=1.9 Hz, 1H), 5.21-5.30(m, 1H), 3.97 (s, 3H), 3.36-3.41 (m, 1H), 3.19-3.25 (m, 1H).

Example 3

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an tan solid according to Example 2,except substituting 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate(1.65 g, 7.97 mmol)[prepared in Preparation 2] for 1,1-dimethylethyl(2-amino-2-phenylethyl)carbamate: LC-MS (ES) m/z 341 (M+H)⁺, ¹H NMR(d₆-DMSO, 400 MHz) δ 8.74 (d, J=8.5 Hz, 1H), 8.05 (bs, 1H), 7.89 (d,J=3.9 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.43 (d, J=3.9 Hz, 1H), 7.26-7.29(m, 3H), 7.20-7.22 (m, 1H), 6.56 (d, J=2.0 Hz, 1H), 4.31-4.42 (m, 1H),2.98-3.01 (m, 2H), 2.91-2.93 (m, 2H).

Example 4

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-{[(2Z)-1-methyl-2-(2-propen-1-ylidene)hydrazino]methyl}-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example2, except substituting 4-bromo-2-thiophenecarboxylic acid (1 g, 4.83mmol) for 5-bromo-2-thiophenecarboxylic acid and 1,1-dimethylethyl(2-amino-3-phenylpropyl)carbamate (1.2 g, 4.83 mmol)[prepared inPreparation 2] for 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate:LC-MS (ES) m/z 441 (M+H)⁺, ¹H NMR (d6-DMSO, 400 MHz) δ 8.98 (bs, 1H),8.29 (s, 1H), 8.17 (bs, 2H), 7.98 (s, 1H), 7.46 (s, 1H), 7.27-7.29 (m,3H), 7.19 (s, 1H), 6.46 (s, 1H), 4.35-4.37 (m, 1H), 3.51 (s, 3H),2.75-3.12 (m, 4H).

Example 5

Preparation ofN-(2-amino-1-phenylethyl)-4-{[(2Z)-1-methyl-2-(2-propen-1-ylidene)hydrazino]methyl}-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example2, except substituting 4-bromo-2-thiophenecarboxylic acid (650 mg, 3.14mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 427 (M+H)⁺,¹H NMR (d6-DMSO, 400 MHz) δ 9.65 (d, J=7.3 Hz, 1H), 8.58 (s, 1H), 8.31(br s, 2H), 7.99 (s, 1H), 7.42-7.51 (m, 2H), 7.72-7.80 (m, 2H),7.20-7.31 (m, 1H), 6.51 (s, 1H), 3.52 (s, 1H), 5.25-5.35 (m, 1H), 3.51(s, 3H), 3.32-3.48 (m, 1H), 3.15-3.21 (m, 1H).

Example 6

Preparation ofN-(2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of 5-bromo-2-thiophenecarboxylic acid (100 mg, 0.48 mmol)in dioxane/H₂O (5:1, 6 mL) was added K₂CO₃ (267 mg, 1.93 mmol),tetrakistriphenylphosphine Pd(0) (28 mg, 24 umol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (94 mg,0.48 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 12 h and was then partitioned between 6N NaOH and DCM. The pH of theaqueous phase was adjusted to ˜3 with 3M HCl and washed several timeswith DCM. The combined organic fractions were dried (Na₂SO₄),concentrated under vacuum and used directly without further purification(˜100 mg, quant.): LC-MS (ES) m/z=209 (M+H)⁺.

b)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethylamine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl(168 mg, 0.48 mmol)[from Preparation 6]. After 16 h, the solution waspartitioned between H₂O and washed with DCM. The combined organicfractions were dried (Na₂SO₄), concentrated and purified via columnchromatography (silica) affording the title compound (74 mg, 28%) as awhite solid: LC-MS (ES) m/z=539 (M+H)⁺.

c)N-(2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(74 mg, 0.14 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (86μL, 2.75 mmol). After stirring for 18 h at RT, the reaction solution wasconcentrated under vacuum and purified via column chromatography(silica, 3% MeOH in DCM (1% NH₄OH)) yielding the title compound.

The neutral compound from above was dissolved in MeOH (2 mL), treatedwith excess 4M HCl in dioxane (500 μL) and concentrated affording theHCl salt of the title compound: LC-MS (ES) m/z=409 (M+H)⁺, ¹H NMR(d6-DMSO, 400 MHz) δ 8.97 (d, J=9.0 Hz, 1H), 8.17 (bs, 1H), 8.00 (d, 3.8Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.55-7.61 (m, 2H), 7.42-7.47 (m 2H),6.56 (d, J=2.0 Hz, 1H), 4.47-4.51 (m, 1H), 4.18 (s, 3H), 3.09-3.11 (m,4H).

Example 7

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example1, except substituting 4,5-dibromo thiophenecarboxylic acid (376 mg,1.32 mmol) for 4,5-dibromo furancarboxylic acid: LC-MS (ES) m/z=419(M+H)⁺, ¹H NMR (d6-DMSO, 400 MHz) δ 8.92 (d, J=8.6 Hz, 1H), 8.03-8.06(m, 2H), 7.56 (d, J=1.9 Hz, 1H), 7.26-7.32 (m, 3H), 7.21-7.23 (m, 1H),6.55 (d, J=1.9 Hz, 1H), 4.32-4.42 (m, 1H), 3.77 (s, 3H), 3.00-3.01 (m,2H), 2.89-2.91 (m, 2H).

Example 8

Preparation ofN-(2-amino-1-phenylethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example1, except substituting 4,5-dibromo thiophenecarboxylic acid (2.2 g, 7.69mmol) for 4,5-dibromo furancarboxylic acid and 1,1-dimethylethyl(2-amino-2-phenylethyl)carbamate (1.1 g, 4.66 mmol) for1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate: LC-MS (ES) m/z=406(M+H)⁺, ¹H NMR (d6-DMSO, 400 MHz) δ 9.47 (d, J=7.9 Hz, 1H), 8.26 (s,1H), 8.17 (bs, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.38-7.46 (m, 3H), 7.30-7.34(m, 1H), 6.56 (d, J=1.6 Hz, 1H), 5.28-5.37 (m, 1H), 3.81 (s, 3H),3.35-3.41 (m, 1H), 3.21-3.28 (m, 1H).

Example 9

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting 5-bromo-2-furancarboxylicacid (58 mg, 0.3 mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS(ES) m/z=393 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ 7.62 (br s, 1H), 7.57 (m,1H), 7.51 (m, 3H), 7.22 (m, 1H), 6.91 (m, 1H), 6.76 (m, 1H), 4.6 (m,1H), 4.07 (m, 3H) and 3.15 (m, 4H).

Example 10

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 6, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl(306 mg, 0.80 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z=409 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.81-2.88 (m,1H) 2.93 (td, J=9.03, 4.93 Hz, 2H) 3.09 (dd, J=13.89, 5.31 Hz, 1H) 4.00(s, 3H) 4.28-4.35 (m, 1H) 6.53 (d, J=2.02 Hz, 1H) 7.32 (d, J=4.04 Hz,1H) 7.45-7.52 (m, 3H) 7.54-7.58 (m, 1H) 7.60 (s, 1H) 7.70 (d, J=4.04 Hz,1H).

Example 11

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-thiophenecarboxylic acid (237 mg, 0.83 mmol) for5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z=488 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.97-3.10 (m, 4H) 3.78 (s, 3H) 4.42-4.54 (m,1H) 6.56 (d, J=2.02 Hz, 1H) 7.45 (t, J=7.58 Hz, 1H) 7.50-7.54 (m, 1H)7.56-7.63 (m, 2H) 7.71 (d, J=7.58 Hz, 1H) 7.92 (s, 1H) 8.76 (d, J=9.09Hz, 1H)

Example 12

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-thiophenecarboxylic acid (237 mg, 0.83 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl(206 mg, 0.535 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z=488 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ ppm 2.97-3.07 (m,1H) 3.10-3.21 (m, 2H) 3.27 (d, J=3.54 Hz, 1H) 3.82 (s, 3H) 4.50-4.59 (m,1H) 6.51 (d, J=2.02 Hz, 1H) 7.50-7.60 (m, 4H) 7.62 (s, 1H) 7.71 (s, 1H).

Example 13

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting 5-bromo-2-furancarboxylicacid (44 mg, 0.23 mmol) for 5-bromo-2-thiophenecarboxylic acid andsubstituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl(87 mg, 0.25 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z=393 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ 7.63 (br s, 1H),7.57 (m, 1H), 7.51 (m, 3H), 7.22 (m, 1H), 6.91 (m, 1H), 6.77 (m, 1H),4.6 (m, 1H), 4.07 (m, 3H) and 3.14 (m, 4H).

Example 14

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-furancarboxylic acid (82 mg, 0.3 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl(115 mg, 0.3 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z=472 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ 7.61 (m, 2H), 7.53(m, 3H), 7.30 (m, 1H), 6.84 (m, 1H), 4.59 (m, 1H), 4.03 (s, 3H), 3.28(m, 1H), 3.17 (m, 2H) and 3.01 (m, 1H)

Example 15

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-furancarboxylic acid (82 mg, 0.3 mmol) for5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z=472 (M+H)⁺, ¹H NMR(CD₃OD, 400 MHz) δ 7.71 (m, 1H), 7.60 (m, 1H), 7.53 (m, 2H), 7.44 (m,1H), 7.33 (m, 1H), 6.88 (m, 1H), 4.7 (m, 1H), 4.06 (s, 3H), 3.25 (m, 3H)and 3.09 (m, 1H).

Example 16

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[2-({[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(0.35 g, 0.67 mmol) [from Example 7] in dioxane/H₂O (5:1, 25:5 mL) wasadded K₂CO₃ (0.28 mg, 2.0 mmol), tetrakistriphenylphosphine Pd(0) (77mg, 0.06 mmol), and trimethylboroxine (0.17 mL, 1.2 mmol). The reactionmixture was heated to 80° C. in a sealed tube for 12 h. The reactionsolution was concentrated under vacuum and purified on silica gel(hexanes/EtOAc, 1:1) to give the title compound (0.10 g, 33%) as a whitesolid: LC-MS (ES) m/z=455 (M+H)⁺.

b)N-[2-amino-1-(phenylmethyl)ethyl]-4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl[2-({[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(0.10 g, 0.22 mmol) was dissolved in MeOH (10 mL) and THF (5 mL) andtreated with 4 M HCl in dioxane (5 mL). After 4 h, the solution wasconcentrated affording the HCl salt of the title compound (68 mg, 91%)as a white powder: LC-MS (ES) m/z=355 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz)δ 7.79 (s, 1H), 7.68 (s, 1H), 7.31 (m, 4H), 7.25 (m, 1H), 6.56 (s, 1H),4.54 (m, 1H), 3.87 (s, 3H), 3.69 (s, 2H), 3.34 (m, 2H), 3.03 (d, J=7.6Hz, 2H) and 2.21 (s, 3H).

Example 17

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 16, except substituting 3-furan boronic acid (0.13g, 1.2 mmole) for trimethylboroxine: LC-MS (ES) m/z=472 (M+H)⁺, ¹H NMR(CD₃OD, 400 MHz) δ 8.13 (s, 1H), 7.81 (s, 1H), 7.53 (m, 2H), 7.34 (m,4H), 7.26 (m, 1H), 6.61 (s, 1H), 6.20 (s, 1H), 4.57 (m, 1H), 3.68 (s,2H), 3.63 (s, 3H), 3.24 (m, 2H) and 3.07 (m, 2H)

Example 18

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 5-chloro-2-thiophenecarboxylate

To a solution of 5-chloro-2-thiophenecarboxylic acid (2.0 g, 12.3 mmol)in dry MeOH (75 mL) was added H₂SO₄ (1 mL). The reaction mixture washeated to 50° C. for 20 h and was then concentrated under vacuum. Theresidue was dissolved in DCM and washed several times with saturatedNaHCO₃ solution. The organic fraction was dried (Na₂SO₄), concentratedunder vacuum and used directly without further purification 21.3 g,quant.): LC-MS (ES) m/z=177 (M+H)⁺.

b) methyl 5-chloro-4-iodo-2-thiophenecarboxylate

To a solution of 5-chloro-2-thiophenecarboxylic acid (5.0 g, 28.0 mmol)in acetic acid (150 mL) was added ZnCl₂ (38 g, 280 mmoles) andbenzyltrimethylammonium dichloroiodate (20.5 g, 58.8 mmole) [Bull. Chem.Soc. Jpn. 64, 2566-2568 (1991)]. The reaction mixture was heated to 70°C. for 48 h and was then concentrated under vacuum. The residue wasextracted with hexanes (2×200 mL) and the hexane solution washed withsaturated NaHCO₃ solution. The organic fractions were dried (Na₂SO₄),concentrated under vacuum and purified on silica gel (hexanes/EtOAc,4:1) to give the title compound (3.8 g, 45%) as a light yellow solid:LC-MS (ES) m/z=302 (M+H)⁺.

c) methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-chloro-4-iodo-2-thiophenecarboxylate (1.75 g,5.8 mmol) in dioxane/H₂O (50:5 mL) was added K₂CO₃ (3.4 g, 24.9 mmol),tetrakistriphenylphosphine Pd(0) (0.96 g, 0.83 mmol), and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (3.4 g,16.5 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 15 h. The reaction solution was concentrated under vacuum andpurified on silica gel (hexanes/EtOAc, 4:1) to give the title compound(0.35 g, 24%) as a yellow oil: LC-MS (ES) m/z=257 (M+H)⁺.

d) 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.30 g,1.17 mmole) in THF (10 mL) and MeOH (10 mL) was added 6N NaOH (5 mL).The reaction solution was heated to 50° C. for 2 hrs. The reactionsolution was concentrated under vacuum, made acidic (pH˜2) with 3N HCl,and extracted with DCM. The organic solution was dried (Na₂SO₄) andconcentrated to a solid (0.22 g) which was used without furtherpurification. LC-MS (ES) m/z=243 (M+H)⁺.

e)5-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.21g, 0.87 mmol), PyBrOP (610 mg, 1.3 mmol) and diisopropylethyl amine(0.76 mL, 4.35 mmol) in DCM (20 mL) at 25° C. was added2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione HCl (380 mg,0.96 mmol)[prepared according to Preparation 5]. After 16 h, thesolution was partitioned between H₂O and washed with DCM. The combinedorganic fractions were dried (Na₂SO₄), concentrated and purified viacolumn chromatography (silica) affording the title compound (200 mg,46%) as a white solid: LC-MS (ES) m/z=505 (M+H)⁺.

f)N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(200 mg, 0.40 mmol) in MeOH/THF (10 mL, 1:1) at RT was added hydrazinehydrate (0.20 mL, 4.0 mmol). After stirring for 24 h at RT, the reactionsolution was concentrated under vacuum and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound as a light yellow solid.

The neutral compound from above was dissolved in DCM (2 mL), treatedwith excess 4M HCl in dioxane (1 mL) and concentrated affording the HClsalt (102 mg) of the title compound: LC-MS (ES) m/z=375 (M+H)⁺, 7.78 (s,1H), 7.63 (s, 1H), 7.31 (m, 4H), 7.26 (m, 1H), 6.55 (s, 1H), 4.54 (m,1H), 3.91 (s, 3H), 3.24 (m, 2H) and 3.03 (m, 2H).

Example 19

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl4-bromo-3-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (500 mg, 1.59 mmol),5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (339 mg,1.75 mmol), Pd(PPh₃)₄ (92 mg, 79.4 μmol) and K₂CO₃ (876 mg, 6.35 mmol)in dioxane (6.6 mL) and H₂O (1.3 mL) were combined in a sealed tube.After 12 h at 80° C., the reaction contents were partitioned betweenH₂O/DCM. The aqueous phase was washed several times with DCM and thecombined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (silica, 0.5% MeOH in DCM) affordingthe title compound (75 mg, 15%) as a brown residue: LCMS (ES) m/z=318(M+H)⁺.

b) methyl4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl4-bromo-3-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(175 mg, 0.554 mmol), MeOH (26 μL, 0.609 mmol), PPh₃ (189 mg, 0.720mmol) in THF (6 mL) at 25° C. was added DEAD (113 μL, 0.720 mmol) in oneportion. After 30 min, the reaction was concentrated and purified viacolumn chromatography (silica, 20% EtOAc in hexanes) affording the titlecompound (135 mg, 74%) as a white solid: LC-MS (ES) m/z=332 (M+H)⁺.

c)1,1-dimethylethyl[2-({[4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

i) A solution of methyl4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(135 mg, 0.410 mmol) in 6N NaOH (4 mL) and THF (4 mL) was stirred in asealed tube at 80° C. After 2 h, the solution was acidified to pH 3using 1N HCl then extracted several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and used directly: LCMS(ES) m/z=318 (M+H)⁺.

ii) To a solution of the crude acid, 1,1-dimethylethyl(2-amino-3-phenylpropyl)carbamate (88 mg, 0.351 mmol)[from Preparation2], diisopropylethyl amine (305 μL, 1.76 mmol) in DCM (3.5 mL) was addedPyBrop (196 mg, 0.422 mmol) in one portion. After 12 h, additionaldiisopropylethyl amine (305 μL, 1.76 mmol) and PyBrop (196 mg, 0.422mmol) were added. After 2 h, the reaction contents were partitionedbetween H₂O/DCM. The aqueous phase was washed several times with DCM andthe combined organic fractions were dried over Na₂SO₄, concentrated andused directly: LCMS (ES) m/z=550 (M+H)⁺.

d)N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[2-({[4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(crude from part e) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After30 min, the solution was concentrated and the residue neutralizedthrough a silica plug (3% MeOH in DCM (1% NH₄OH)) affording the freebase of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound as the HCl salt: LC-MS (ES)m/z 450 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.07 (br. s., 3H) 7.85(d, J=8.84 Hz, 1H) 7.58 (d, J=2.02 Hz, 1H) 7.32 (d, J=7.07 Hz, 2H)7.26-7.29 (m, 2H) 7.20-7.24 (m, 1H) 6.54 (d, J=2.02 Hz, 1H) 4.50-4.55(m, 1H) 3.79 (d, J=6.82 Hz, 3H) 3.74 (d, J=6.57 Hz, 1H) 3.17 (s, 1H)2.98-3.10 (m, 4H).

Example 20

Preparation ofN-[3-amino-1-(phenylmethyl)propyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (1 g, 3.5 mmol)in dioxane/H₂O (5:1, 18 mL) was added K₂CO₃ (1.9 g, 13.98 mmol),tetrakistriphenylphosphine Pd(0) (201 mg, 0.175 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (678 mg,3.5 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 12 h and was then partitioned between 6N NaOH and DCM. The pH of theaqueous phase was adjusted to ˜3 with 3M HCl and washed several timeswith DCM. The combined organic fractions were dried (Na₂SO₄),concentrated under vacuum and used directly without further purification(˜1 g, quant.): LC-MS (ES) m/z=288 (M+H)⁺.

b)1,1-dimethylethyl[3-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-4-phenylbutyl]carbamate

To a solution of4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (250 mg,0.874 mmol), PyBrOP (489 mg, 8.74 mmol) and diisopropylethyl amine (762μL, 4.37 mmol) in DCM (8 mL) at 25° C. was added 1,1-dimethylethyl(3-amino-4-phenylbutyl)carbamate (230 mg, 0.874 mmol)[prepared accordingto Preparation 8]. After 16 h, the solution was partitioned between H₂Oand washed with DCM. The combined organic fractions were dried (Na₂SO₄),concentrated and purified via column chromatography (silica) affordingthe title compound (130 mg, 29%) as a white solid: LC-MS (ES) m/z=533(M+H)⁺.

c)N-[3-amino-1-(phenylmethyl)propyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[3-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-4-phenylbutyl]carbamate(130 mg, 0.24 mmol) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After30 min, the solution was concentrated and the residue neutralizedthrough a silica plug (3% MeOH in DCM (1% NH₄OH)) affording the freebase of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (40 mg, 40%) as the HClsalt: LC-MS (ES) m/z 433 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.68(d, J=8.59 Hz, 1H) 7.97 (s, 1H) 7.77 (br s, 3H) 7.57 (d, J=2.02 Hz, 1H)7.28 (d, J=2.27 Hz, 3H) 7.25-7.32 (m, 2H) 6.55 (d, J=2.02 Hz, 1H)4.17-4.24 (m, 1H) 3.78 (s, 3H) 2.77-2.89 (m, 4H) 1.85-1.92 (m, 1H) 1.81(td, J=9.54, 4.93 Hz, 1H).

Example 21

Preparation of4-bromo-N-[2-(methylamino)-1-phenylethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 1, except substituting 1,1-dimethylethyl(2-amino-2-phenylethyl)methylcarbamate (1 g, 4.02 mmol) [Preparedaccording to the procedure of Preparation 1] for 1,1-dimethylethyl(2-amino-2-phenylethyl)carbamate and substituting4,5-dibromo-2-thiophenecarboxylic acid (1.89 g, 6.6 mmol) for4,5-dibromo-2-furancarboxylic acid: LCMS (ES) m/z 420 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.64 (d, J=8.34 Hz, 1H) 8.91 (br. s., 1H) 8.33(s, 1H) 7.58 (d, J=2.02 Hz, 1H) 7.42-7.50 (m, 2H) 7.38-7.42 (m, 2H) 7.34(d, J=7.07 Hz, 1H) 6.56 (d, J=2.02 Hz, 1H) 5.37-5.44 (m, 1H) 3.79 (s,3H) 3.47-3.54 (m, 1H) 3.33 (td, J=8.46, 3.79 Hz, 1H) 2.63 (t, J=5.31 Hz,3H).

Example 22

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 1, except substituting4-bromo-5-methyl-2-thiophenecarboxylic acid (81 mg, 0.368 mmol)[fromPreparation 10] for 4,5-dibromo-2-furancarboxylic acid: LC-MS (ES) m/z355 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (d, J=8.34 Hz, 1H) 8.15(br. s., 3H) 8.00 (s, 1H) 7.52 (d, J=1.77 Hz, 1H) 7.24-7.31 (m, 4H)7.17-7.23 (m, 1H) 6.36 (d, J=1.77 Hz, 1H) 4.35 (d, J=3.03 Hz, 1H) 3.78(s, 3H) 3.03 (dd, J=6.82, 2.53 Hz, 1H) 2.93-2.99 (m, 2H) 2.90 (d, J=6.06Hz, 1H) 2.38 (s, 3H).

Example 23

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 1, except substituting4-bromo-5-chloro-2-thiophenecarboxylic acid (250 mg, 1.04 mmol)[fromPreparation 11] for 4,5-dibromo-2-furancarboxylic acid: LC-MS (ES) m/z375 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, J=8.59 Hz, 1H) 8.14(s, 3H) 8.10 (br. s., 1H) 7.55 (d, J=1.77 Hz, 1H) 7.25-7.32 (m, 4H) 7.21(dd, J=6.19, 2.40 Hz, 1H) 6.48 (d, J=2.02 Hz, 1H) 4.35 (d, J=8.59 Hz,1H) 3.84 (s, 3H) 2.99 (d, J=10.86 Hz, 1H) 2.89-2.96 (m, 3H).

Example 24

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of 4-bromo-2-thiophenecarboxylic acid (1 g, 4.83 mmol) indioxane/H₂O (5:1, 16 mL) was added K₂CO₃ (2.7 g, 19 mmol),tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g,6.27 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.241mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole(1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitionedbetween 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3with 3M HCl and washed several times with DCM. The combined organicfractions were dried (Na₂SO₄), concentrated under vacuum and useddirectly without further purification (˜1 g, quant.): LCMS (ES) m/z=209(M+H)⁺.

b) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(600 mg, 2.88 mmol) and N-chlorosuccinimide (384 mg, 2.88 mmol) in THF(14 mL) was stirred in a sealed tube at 70° C. After 1 h, the solutionwas partitioned between H₂O-DCM, the aqueous phase was adjusted to pH 3and the aqueous phase was washed several times with DCM. The combinedorganic fractions were dried (Na₂SO₄), concentrated under vacuum andused directly without further purification (698 mg, quant.): LCMS (ES)m/z=243 (M+H)⁺.

c)1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (350mg, 1.45 mmol), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (362mg, 1.45 mmol)[from Preparation 2] and diisopropylethyl amine (1.3 mL,7.23 mmol) in DCM (7 mL) was added PyBrop (809 mg, 1.74 mmol) in oneportion. After 1 h, the reaction contents were partitioned betweenH₂O/DCM. The aqueous phase was washed several times with DCM and thecombined organic fractions were dried over Na₂SO₄, concentrated and useddirectly: LCMS (ES) m/z=476 (M+H)⁺.

d)N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After30 min, the solution was concentrated and the residue neutralizedthrough a silica plug (4% MeOH in DCM (1% NH₄OH)) affording the freebase of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (90 mg, 17%-2steps) as theHCl salt: LCMS (ES) m/z 476 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.75(d, J=8.08 Hz, 1H) 8.10 (d, J=1.52 Hz, 2H) 8.08 (s, 3H) 7.68 (s, 1H)7.26-7.32 (m, 4H) 7.22 (dd, J=6.06, 2.53 Hz, 1H) 4.39 (br. s., 1H) 3.87(s, 3H) 2.91 (d, J=7.33 Hz, 4H).

Example 25

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of 4-bromo-5-chloro-2-thiophenecarboxylic acid (1.3 g,5.42 mmol), PyBrOP (3 g, 6.5 mmol) and diisopropylethyl amine (4.7 mL,27.1 mmol) in DCM (54 mL) at 25° C. was added2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(2.0 g, 5.42 mmol)[prepared in Preparation 6]. After 1 h, the solutionwas partitioned between H₂O and washed with DCM. The combined organicfractions were dried (Na₂SO₄), concentrated and used directly: LCMS (ES)m/z=572 (M+H)⁺.

b) 1,1-dimethylethyl{(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

To a solution of4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(crude from part a) in THF-MeOH (1:1, 20 mL) was added hydrazine (1.59mL, 54.2 mmol). After 12 h, the solution was filtered and the filtrateconcentrated, dry loaded onto silica and purified via columnchromatography (2% MeOH in DCM (1% NH₄OH)) affording the free base whichwas dissolved in THF (25 mL) and treated with Boc₂O (1.2 g, 5.31 mmol).After 30 min the solution was concentrated affording a white powder ofthe title compound (800 mg, 27%-3 steps): LCMS (ES) m/z=542 (M+H)⁺.

c) 1,1-dimethylethyl{(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

To a solution of 1,1-dimethylethyl{(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate(750 mg, 1.38 mmol) in dioxane/H₂O (5:1, 6 mL) was added K₂CO₃ (762 mg,5.52 mmol), tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol), and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (373 mg,1.8 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 2 h where additional tetrakistriphenylphosphine Pd(0) (80 mg, 69umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole(373 mg, 1.8 mmol) were added. After 12 h, the solution was poured ontoH₂O (100 mL) and extracted with DCM. The organics were dried (Na₂SO₄),concentrated under vacuum, and purified on silica gel (hexanes/EtOAc,1:1) to give the title compound (194 mg, 26%) as a white solid: LC-MS(ES) m/z=544.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl{(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate(194 mg, 0.357 mmol) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at25° C. After 30 min, the solution was concentrated with a tolueneazeotrope and the residue neutralized through a silica plug (2-5% MeOHin DCM (1% NH₄OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (134 mg, 85%) as the HClsalt: LCMS (ES) m/z 444 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.10 (d,J=9.09 Hz, 1H) 8.11 (s, 1H) 8.10 (bs, 3H) 7.70 (d, J=8.08 Hz, 1H) 7.57(d, J=2.02 Hz, 2H) 7.43 (s, 1H) 6.49 (d, J=2.02 Hz, 1H) 4.47 (br. s.,1H) 3.85 (s, 3H) 3.06 (d, J=8.34 Hz, 4H).

Example 26

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

The title compound was prepared as white solid according to theprocedure of Example 24, except substituting2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(288 mg, 0.826 mmol)[from Preparation 6] for 1,1-dimethylethyl(2-amino-3-phenylpropyl)carbamate: LCMS (ES) m/z 444 (M+H)⁺.

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(150 mg, 0.262 mmol) in THF-MeOH (1:1, 2 mL) was added hydrazine (123uL, 2.62 mmol). After 12 h, the solution was filtered and the filtratewas concentrated, dry loaded onto silica and purified via columnchromatography (2% MeOH in DCM (1% NH₄OH)) affording the free base ofthe title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (30 mg, 26%) as the HClsalt: LCMS (ES) m/z 444 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.69 (s,1H) 8.11 (d, J=1.26 Hz, 1H) 8.03 (d, J=1.26 Hz, 1H) 7.93 (bs, 3H) 7.69(s, 2H) 7.53-7.59 (m, 2H) 7.44 (d, J=4.80 Hz, 1H) 4.49 (br. s., 1H) 3.87(s, 3H) 2.99-3.12 (m, 4H).

Example 27

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 24, except substituting4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol)[fromPreparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid and substituting NBS (325 mg, 2.43 mmol) for NCS: LCMS (ES) m/z 434(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.65 (br. s., 1H) 8.01 (br. s.,3H) 7.80 (s, 1H) 7.70 (s, 1H) 7.25-7.32 (m, 4H) 7.21 (td, J=6.19, 2.78Hz, 1H) 4.31-4.35 (m, 1H) 3.71 (s, 3H) 2.86-2.92 (m, 4H) 2.33 (s, 3H).

Example 28

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 26, except substituting4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol)[fromPreparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid and substituting NBS (325 mg, 2.43 mmol) for NCS: LCMS (ES) m/z 502(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.81 (br. s., 1H) 8.05 (br. s.,3H) 7.83-7.90 (m, 1H) 7.67-7.74 (m, 2H) 7.53-7.60 (m, 2H) 7.39-7.47 (m,1H) 4.48 (d, J=5.05 Hz, 1H) 3.68-3.76 (m, 3H) 3.01-3.08 (m, 4H) 2.33 (s,3H).

Example 29

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 26, except substituting4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol)[fromPreparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid: LCMS (ES) m/z 457 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.76(br. s., 1H) 8.03 (br. s., 3H) 7.86 (s, 1H) 7.70 (s, 2H) 7.53-7.60 (m,2H) 7.39-7.47 (m, 1H) 4.46 (d, J=9.35 Hz, 1H) 3.72 (s, 3H) 3.03-3.10 (m,4H) 2.34 (s, 3H).

Example 30

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 24, except substituting4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol)[fromPreparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid: LCMS (ES) m/z 389 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.67(br. s., 1H) 8.01 (br. s., 3H) 7.82 (s, 1H) 7.70 (s, 1H) 7.25-7.32 (m,4H) 7.19-7.23 (m, 1H) 4.31-4.38 (m, 1H) 3.71 (s, 3H) 2.97 (br. s., 2H)2.89 (t, J=6.19 Hz, 2H) 2.34 (s, 3H).

Example 31

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 1,1-dimethylethyl{(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

A solution of 1,1-dimethylethyl{(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate(110 mg, 0.202 mmol)[prepared in Example 25] and N-chlorosuccinimide (35mg, 0.263 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C.After 1 h, the solution was partitioned between H₂O-DCM and the aqueousphase was washed several times with DCM. The combined organic fractionswere dried (Na₂SO₄), concentrated under vacuum and used directly withoutfurther purification: LCMS (ES) m/z=578 (M+H)⁺.

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl{(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate(crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at25° C. After 30 min, the solution was concentrated and the residueneutralized through a silica plug (5% MeOH in DCM (1% NH₄OH)) affordingthe free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (43 mg, 44%-2 steps) as theHCl salt: LCMS (ES) m/z 478 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.10(d, J=8.84 Hz, 1H) 8.06 (s, 4H) 7.75 (s, 1H) 7.70 (d, J=7.83 Hz, 1H)7.54-7.61 (m, 2H) 7.43 (t, J=7.45 Hz, 1H) 4.47 (t, J=8.84 Hz, 1H) 3.78(s, 3H) 2.98-3.12 (m, 4H).

Example 32

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamidea) 1,1-dimethylethyl{(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

A solution of 1,1-dimethylethyl{(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate(121 mg, 0.22 mmol)[prepared in Example 25] and N-bromosuccinimide (52mg, 0.290 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C.After 1 h, the solution was partitioned between H₂O-DCM and the aqueousphase was washed several times with DCM. The combined organic fractionswere dried (Na₂SO₄), concentrated under vacuum and used directly withoutfurther purification: LCMS (ES) m/z=622 (M+H)⁺.

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl{(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate(crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at25° C. After 30 min, the solution was concentrated and the residueneutralized through a silica plug (5% MeOH in DCM (1% NH₄OH)) affordingthe free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (42 mg, 44%-2 steps) as theHCl salt: LCMS (ES) m/z 522 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.13(d, J=9.09 Hz, 1H) 8.17 (br. s., 1H) 8.05 (s, 3H) 7.75 (s, 1H) 7.69 (d,J=7.83 Hz, 1H) 7.54-7.61 (m, 2H) 7.43 (t, J=7.58 Hz, 1H) 4.46 (d, J=9.60Hz, 1H) 3.78 (s, 3H) 2.99-3.13 (m, 4H).

Example 33

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

The title compound was prepare as an orange oil according to Example 24,except substituting N-bromosuccinimide (1 g, 5.77 mmol) forN-chlorosuccinimide: LCMS (ES) m/z 288 (M+H)⁺.

b) 4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (688 mg,2.41 mmol) in dioxane/H₂O (5:1, 12 mL) was added K₂CO₃ (1.3 g, 9.6mmol), tetrakistriphenylphosphine Pd(0) (139 mg, 0.120 mmol), and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (293 mg,2.41 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 2 h where additional tetrakistriphenylphosphine Pd(0) (139 mg, 0.120mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole(293 mg, 2.41 mmol) were added. After 12 h, the solution was poured ontoH₂O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phasewas extracted several times with DCM and the combined organic fractionswere dried (Na₂SO₄) and concentrated affording the title compound whitewas used directly without further purification: LC-MS (ES) m/z=284(M+H)⁺.

c)1,1-dimethylethyl[2-({[4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (341mg, 1.2 mmol), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (300mg, 1.2 mmol)[from Preparation 2], diisopropylethyl amine (1 mL, 6.01mmol) in DCM (6 mL) was added PyBrop (673 mg, 1.44 mmol) in one portion.After 1 h, the reaction contents were partitioned between H₂O/DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and used directly: LCMS(ES) m/z=517 (M+H)⁺.

d)N-[2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[2-({[4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After30 min, the solution was concentrated and the residue neutralizedthrough a silica plug (4% MeOH in DCM (1% NH₄OH)) affording the freebase of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (105 mg, 21%-3steps) as theHCl salt: LCMS (ES) m/z 417 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.82(d, J=8.34 Hz, 1H) 8.14 (br. s., 3H) 7.96 (s, 1H) 7.90 (d, J=1.26 Hz,1H) 7.82 (s, 1H) 7.29 (s, 1H) 7.25 (t, J=8.46 Hz, 9H) 4.34 (dd, J=7.45,5.68 Hz, 1H) 3.75 (s, 3H) 2.94-3.00 (m, 2H) 2.89 (dd, J=6.82, 5.31 Hz,2H).

Example 34

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 33, except substituting2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(420 mg, 1.2 mmol) [from Preparation 6] for 1,1-dimethylethyl(2-amino-3-phenylpropyl)carbamate: LCMS (ES) m/z 615 (M+H)⁺.

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(crude from part a) in THF-MeOH (1:1, 10 mL) was added hydrazine (384uL, 12 mmol). After 12 h, the solution was filtered and the filtrate wasconcentrated, dry loaded onto silica and purified via columnchromatography (2% MeOH in DCM (1% NH₄OH)) affording the free base ofthe title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (40 mg, 7%) as the HCl salt:LCMS (ES) m/z 485 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.78 (d,J=9.09 Hz, 1H) 8.05 (br. s., 3H) 7.91 (dd, J=9.09, 1.26 Hz, 2H) 7.83 (s,1H) 7.69 (d, J=7.33 Hz, 1H) 7.50-7.53 (m, 1H) 7.43 (d, J=7.58 Hz, 1H)7.47 (t, J=6.82 Hz, 1H) 7.23-7.30 (m, 4H) 7.22 (s, 1H) 4.47 (br. s., 1H)3.75 (s, 3H) 3.01 (d, J=8.08 Hz, 4H).

Example 35

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamidea) methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-bromo-4-methyl-2-thiophenecarboxylate (1 g,4.25 mmol) in dioxane/H₂O (5:1, 20 mL) was added K₂CO₃ (2.3 g, 17 mmol),bis(tri-t-butylphosphine)palladium(0) (108 mg, 0.213 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g,5.52 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.241mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole(1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitionedbetween H₂O-DCM and the aqueous phase was washed several times with DCM.The combined organic fractions were dried over Na₂SO₄, concentrated andused directly without further purification: LCMS (ES) m/z=237 (M+H)⁺.

b) 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of methyl4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (crude frompart a) in THF (4 mL) and 6N NaOH (4 mL) was heated to 70° C. After 1 h,the solution was poured onto H₂O and the pH was adjusted to ˜4 withaqueous HCl. The aqueous phase was extracted several times with DCM andthe combined organic fractions were dried (Na₂SO₄) and concentratedaffording the title compound as a white solid which was used directlywithout further purification: LCMS (ES) m/z=223 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 27, except substituting4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (424mg, 1.92 mmol) for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid: LCMS (ES) m/z 457 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (d,J=8.84 Hz, 1H) 8.05 (br. s., 3H) 7.84 (s, 1H) 7.74 (s, 1H) 7.71 (d,J=8.08 Hz, 1H) 7.56-7.63 (m, 2H) 7.44 (t, J=7.20 Hz, 1H) 4.47-4.54 (m,1H) 3.70 (s, 3H) 2.93-3.12 (m, 4H) 2.10 (s, 3H).

Example 36

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamidea) methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-bromo-4-methyl-2-thiophenecarboxylate (1 g,4.25 mmol) in dioxane/H₂O (5:1, 20 mL) was added K₂CO₃ (2.3 g, 17 mmol),bis(tri-t-butylphosphine)palladium(0) (108 mg, 0.213 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g,5.52 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.24mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole(1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitionedbetween H₂O-DCM and the aqueous phase was washed several times with DCM.The combined organic fractions were dried over Na₂SO₄, concentrated andused directly without further purification: LCMS (ES) m/z=237 (M+H)⁺.

b) 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of methyl4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (crude frompart a) in THF (4 mL) and 6N NaOH (4 mL) was heated to 70° C. After 1 h,the solution was poured onto H₂O and the pH was adjusted to ˜4 withaqueous HCl. The aqueous phase was extracted several times with DCM andthe combined organic fractions were dried (Na₂SO₄) and concentratedaffording the title compound white was used directly without furtherpurification: LCMS (ES) m/z=223 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 26, except substituting4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (424mg, 1.92 mmol) for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid and substituting N-bromosuccinimide (376 mg, 2.11 mmol) forN-chlorosuccinimide: LCMS (ES) m/z 502 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.84 (d, J=9.09 Hz, 1H) 8.05 (br. s., 3H) 7.83 (s, 1H) 7.67-7.74(m, 2H) 7.60 (q, J=7.83 Hz, 2H) 7.40-7.47 (m, 1H) 4.50 (d, J=4.04 Hz,1H) 3.71 (s, 3H) 2.98-3.12 (m, 4H) 2.09 (s, 3H).

Example 37

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 4-bromo-2-thiophenecarboxylate

To a solution of 4-bromo-2-thiophenecarboxylic acid (4 g, 19 mmol) inMeOH (100 mL) was added H₂SO₄ (5 mL) dropwise at 25° C. The solution wasstirred for 12 h at 50° C. and was poured into ice-H₂O and the pH wasadjusted to ˜11 with aqueous NaOH. The aqueous phase was extractedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and used directly (4.27 g, quant.): LCMS (ES)m/z 222 (M+H)⁺.

b) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-2-thiophenecarboxylate (1 g, 4.52 mmol)in dioxane/H₂O (5:1, 16 mL) was added K₂CO₃ (2.7 g, 19 mmol),bis(tri-t-butylphosphine)palladium(0) (116 mg, 0.226 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g,5.88 mmol). The reaction mixture was heated to 80° C. in a sealed tube.After 1 h, the reaction was partitioned between H₂O-DCM and the aqueousphase was extracted several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and used directly: LCMS(ES) m/z 223 (M+H)⁺.

c) methyl 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(330 mg, 1.49 mmol) and Selectfluor® (793 mg, 2.23 mmol) in THF (7 mL)and H₂O (500 uL) was stirred in a sealed tube at 70° C. After 1 h,additional selectfluor (793 mg, 2.23 mmol) was added and the solutionstirred an additional 12 h. The reaction mixture was then partitionedbetween H₂O-DCM, the aqueous phase was washed several times with DCM.The combined organic fractions were dried (Na₂SO₄), concentrated andpurified via column chromatography (silica, 20% EtOAc in hexanes)affording the title compound (126 mg, 33%) as a white solid: LCMS (ES)m/z=241 (M+H)⁺.

d) 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of methyl4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (126 mg,0.53 mmol) in THF (1 mL) and 6N NaOH (1 mL) was heated to 70° C. After 1h, the solution was poured onto H₂O and the pH was adjusted to ˜4 withaqueous HCl. The aqueous phase was extracted several times with DCM andthe combined organic fractions were dried (Na₂SO₄) and concentratedaffording the title compound white was used directly without furtherpurification: LCMS (ES) m/z=227 (M+H)⁺.

e)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (84 mg,0.372 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(130 mg, 0.372 mmol)[from Preparation 6], diisopropylethyl amine (323uL, 1.86 mmol) in DCM (4 mL) was added PyBrop (208 mg, 0.446 mmol) inone portion. After 1 h, the reaction contents were partitioned betweenH₂O/DCM. The aqueous phase was washed several times with DCM and thecombined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (silica, 0.5% MeOH-DCM) affording thetitle compound (135 mg, 65%) as a white solid: LCMS (ES) m/z=557 (M+H)⁺.

f)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(135 mg, 0.242 mmol) in THF-MeOH (1:1, 2 mL) was added hydrazine (75 uL,2.42 mmol). After 12 h, the solution was filtered and the filtrate wasconcentrated, dry loaded onto silica and purified via columnchromatography (3% MeOH in DCM (1% NH₄OH)). The title compound wasfurther purified via Gilson reverse phase chromatography using 5-95%mobile phase gradient affording the TFA-salt of the title compound whichwas neutralized through a silica plug ((5% MeOH in DCM (1% NH₄OH)) thentransferred to the HCl salt using excess 4M HCl in dioxane (40 mg, 26%):LCMS (ES) m/z 427 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) d ppm 8.88 (d,J=8.84 Hz, 1H) 8.13 (s, 1H) 8.06 (bs, 3H) 7.70 (d, J=7.83 Hz, 1H)7.55-7.62 (m, 3H) 7.54 (br. s., 1H) 7.41 (d, J=2.53 Hz, 1H) 4.49 (d,J=5.05 Hz, 1H) 3.92 (s, 3H) 2.99-3.11 (m, 4H).

Example 38

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 37, except substituting methyl4-bromo-5-methyl-2-thiophenecarboxylate (1 g, 4.26 mmol)[fromPreparation 11] for methyl 4-bromo-2-thiophenecarboxylate: LCMS (ES) m/z441 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (d, J=9.60 Hz, 1H) 8.03(br s, 3H) 7.91 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.62 (d, J=4.55 Hz, 1H)7.52-7.59 (m, 2H) 7.39-7.46 (m, 1H) 4.47 (br. s., 1H) 3.74 (s, 3H) 3.06(br. s., 4H) 2.36 (s, 3H).

Example 39

Preparation ofN-[1-(aminomethyl)-3-phenylpropyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 20, except substituting 1,1-dimethylethyl(2-amino-4-phenylbutyl)carbamate (0.44 g, 1.7 mmol) [from Preparation 4]for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES)m/z=435 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 1.92-2.22 (m, 2H) 2.71-2.82(m, 2H) 3.02-3.11 (m, 1H) 3.12-3.24 (m, 1H) 3.88 (s, 3H) 4.30 (s, 1H)6.59 (d, J=1.77 Hz, 1H) 7.17 (t, J=7.07 Hz, 1H) 7.22-7.29 (m, 4H) 7.67(d, J=1.77 Hz, 1H) 7.85 (s, 1H).

Example 40

Preparation ofN-[1-(aminomethyl)-3-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 20, except substituting5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (223 mg, 1.07mmol) for 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid and substituting 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate(0.51 g, 1.9 mmol) [from Preparation 4] for 1,1-dimethylethyl(3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 355 (M+H)⁺, ¹H NMR (400MHz, MeOD) δ ppm 1.87-1.99 (m, 2H) 2.69-2.91 (m, 4H) 4.00-4.07 (m, 3H)4.08-4.16 (m, 1H) 6.56 (d, J=2.02 Hz, 1H) 7.15 (t, J=6.95 Hz, 1H)7.20-7.28 (m, 4H) 7.35 (d, J=3.79 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.79(d, J=3.79 Hz, 1H).

Example 41

Preparation of4-bromo-N-[3-(methylamino)-1-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 20, except substituting 1,1-dimethylethyl(3-amino-3-phenylpropyl)methylcarbamate (289 mg, 1.09 mmol) [fromPreparation 12] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate:LC-MS (ES) m/z 435 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.12-2.23 (m,2H) 2.45-2.52 (m, 3H) 2.64-2.74 (m, 1H) 2.76 (dd, J=8.72, 5.94 Hz, 1H)3.77-3.88 (m, 3H) 5.10-5.20 (m, 1H) 6.52 (d, J=2.02 Hz, 1H) 7.30 (d,J=6.82 Hz, 1H) 7.35-7.45 (m, 4H) 7.57 (d, J=1.77 Hz, 1H) 7.89 (s, 1H).

Example 42

Preparation ofN-[3-(methylamino)-1-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 20, except substituting 1,1-dimethylethyl(3-amino-3-phenylpropyl)methylcarbamate (430 mg, 1.63 mmol) [fromPreparation 12] for 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamateand substituting 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(224 mg, 1.08 mmol) for4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid: LC-MS(ES) m/z 355 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.18-2.28 (m, 2H) 2.55(s, 3H) 2.77-2.85 (m, 1H) 2.87 (dd, J=8.84, 5.81 Hz, 1H) 4.01 (s, 3H)5.19 (dd, J=8.59, 6.57 Hz, 1H) 6.55 (d, J=2.02 Hz, 1H) 7.31 (d, J=7.07Hz, 1H) 7.34-7.41 (m, 3H) 7.44-7.47 (m, 2H) 7.50 (d, J=2.02 Hz, 1H) 7.85(d, J=4.04 Hz, 1H).

Example 43

Preparation of4-bromo-N-[2-(methylamino)-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 20, except substituting 1,1-dimethylethyl(2-amino-3-phenylpropyl)methylcarbamate (0.26 g, 1.09 mmol) [fromPreparation 12] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate:LC-MS (ES) m/z 435 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.60 (s, 3H)2.90-3.01 (m, 2H) 3.06 (d, J=6.57 Hz, 2H) 3.83 (s, 3H) 4.48-4.58 (m, 1H)6.52 (d, J=1.77 Hz, 1H) 7.17-7.27 (m, 1H) 7.27-7.33 (m, 4H) 7.57 (d,J=2.02 Hz, 1H) 7.77 (s, 1H).

Example 44

Preparation ofN-((1S)-2-amino-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example6, except substituting2-{(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(0.22 g, 0.62 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl.The reaction mixture was absorbed onto silica and purified via columnchromatography to yield the title compound, which was further purifiedby Gilson reverse phase chromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA)to afford the TFA salt: LC-MS (ES) m/z 489 (M+H)⁺, ¹H NMR (400 MHz,MeOD) δ ppm 3.04-3.30 (m, 4H) 3.81-3.85 (m, 3H) 4.59 (dd, J=6.32, 3.28Hz, 1H) 6.52 (d, J=2.02 Hz, 1H) 7.50 (d, J=8.08 Hz, 2H) 7.58 (d, J=2.02Hz, 1H) 7.64 (d, J=8.08 Hz, 2H) 7.73 (s, 1H).

Example 45

Preparation ofN-[1-(aminomethyl)-2-methyl-2-phenylpropyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (194 mg,0.68 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acidand substituting2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (0.20 g,0.58 mmol) [prepared according to preparation 16] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl.The reaction mixture was absorbed onto silica and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound, which was further purified by Gilson reverse phasechromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA) to afford the TFA salt:LC-MS (ES) m/z 448 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 1.40 (s, 3H)1.47 (s, 3H) 2.85-2.92 (m, 1H) 3.01 (d, J=11.37 Hz, 1H) 3.83-3.86 (m,3H) 4.74 (dd, J=11.37, 2.27 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H) 7.28 (t,J=7.33 Hz, 1H) 7.41 (t, J=7.71 Hz, 3H) 7.52 (d, J=7.58 Hz, 2H) 7.59 (d,J=2.02 Hz, 1H) 7.89 (s, 1H).

Example 46

Preparation ofN-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (135 mg,0.47 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acidand substituting2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(153 mg, 0.44 mmol) [prepared according to the procedure of Preparation6] forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine.The reaction mixture was absorbed onto silica and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound, which was further purified by Gilson reverse phasechromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA) to afford the TFA salt:LC-MS (ES) m/z 491 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.03 (dd,J=13.89, 9.35 Hz, 1H) 3.14-3.21 (m, 1H) 3.21-3.29 (m, 2H) 3.84 (s, 3H)4.62-4.70 (m, 1H) 6.53 (d, J=2.02 Hz, 1H) 7.28-7.32 (m, 1H) 7.33-7.37(m, 1H) 7.51 (d, J=2.02 Hz, 1H) 7.58 (d, J=2.02 Hz, 1H) 7.73-7.76 (m,1H).

Example 47

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a pale yellow solid according to theprocedure of Example 30, except substituting4,5-dibromo-2-thiophenecarboxylic acid (2.84 g, 9.9 mmol) for4-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 457 (M+H)⁺, ¹H NMR(400 MHz, MeOD) δ ppm 2.95-3.07 (m, 4H) 3.75 (s, 3H) 4.44 (dd, J=6.44,4.93 Hz, 1H) 7.18-7.24 (m, 1H) 7.27-7.32 (m, 4H) 7.59 (s, 1H) 7.86 (s,1H).

Example 48

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamidea) 4,5-dibromo-1-methyl-1H-pyrrole-2-carboxylic Acid

NBS (6.3 g, 35.4 mmol) was added in portions over 15 minutes to astirred solution of 1-methyl-1H-pyrrole-2-carboxylic acid (2.1 g, 16.78mmol) in DMF (30 mL) at 0° C. Upon complete addition the mixture wasslowly brought to 70° C. After 1 h, the solution was partitioned betweenH₂O—CHCl₃, the aqueous phase was adjusted to pH 3 and the aqueous phasewas washed several times with CHCl₃. The combined organic fractions weredried (Na₂SO₄) and concentrated under vacuum to yield a 3:4 mixture of5-bromo-1-methyl-1H-pyrrole-2-carboxylic acid and4,5-dibromo-1-methyl-1H-pyrrole-2-carboxylic acid (3.4 g) which was useddirectly without further purification: LCMS (ES) m/z=206/286 (M+H)⁺.

b) 1,1-dimethylethyl(2-{[(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate

To a solution of 5-bromo-1-methyl-1H-pyrrole-2-carboxylic acid and4,5-dibromo-1-methyl-1H-pyrrole-2-carboxylic acid (1.3 g),1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (1.2 g, 4.8 mmol)[from Preparation 2] and PyBrop (2.6 g, 5.6 mmol) in CHCl₃ (30 mL) wasadded diisopropylethyl amine (2.8 mL, 16.1 mmol). The reaction mixturewas stirred overnight, adsorbed onto silica and purified via columnchromatography [1:3 EtOAc/hexanes] to give a 1:1 mixture of1,1-dimethylethyl(2-{[(5-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamateand 1,1-dimethylethyl(2-{[(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate(800 mg): LCMS (ES) m/z=438/518 (M+H)⁺.

c)1,1-dimethylethyl[2-({[4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of a 1:1 mixture of 1,1-dimethylethyl(2-{[(5-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamateand 1,1-dimethylethyl(2-{[(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate(307 mg) in dioxane/H₂O (5:1, 5.6 mL) was added Cs₂CO₃ (800 mg, 2.5mmol), tetrakistriphenylphosphine Pd(0) (44 mg, 0.04 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(157 mg, 0.75 mmol). The reaction mixture was heated to 80° C. in asealed tube for 2 h after which additional tetrakistriphenylphosphinePd(0) (20 mg, 0.02 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (177 mg,0.85 mmol) were added. After 12 h, the reaction mixture was adsorbedonto silica and purified via column chromatography to give two isomers:the title compound1,1-dimethylethyl[2-({[4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate(17 mg, 0.033 mmol) and1,1-dimethylethyl[2-({[1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate(20 mg, 0.05 mmol).

d)N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

1,1-dimethylethyl[3-{[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-(phenylmethyl)propyl]carbamate(0.045 g, 0.09 mmol) dissolved in CHCl₃ (4 mL) and MeOH (1 mL) wastreated with 4 M HCl in dioxane (2 mL). After stirring for 18 h at RT,the reaction solution was adsorbed onto silica and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound as a white solid.

The neutral compound from above was dissolved in MeOH (2 mL), treatedwith excess 2M HCl in Et₂O (150 μL) and concentrated affording the HClsalt of the title compound: LC-MS (ES) m/z 418 (M+H)⁺, ¹H NMR (400 MHz,MeOD) δ ppm 2.76-2.98 (m, 4H) 3.57 (d, J=2.78 Hz, 3H) 3.71 (d, J=1.26Hz, 3H) 4.28 (ddd, J=8.27, 5.12, 2.78 Hz, 1H) 6.44 (dd, J=7.58, 2.02 Hz,1H) 6.85 (s, 1H) 7.18-7.24 (m, 1H) 7.27-7.32 (m, 4H) 7.61 (d, J=2.02 Hz,1H).

Example 49

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

1,1-dimethylethyl[2-({[1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate(20 mg, 0.05 mmol) [prepared in Example 48] in CHCl₃ (4 mL) and MeOH (1mL) was treated with 4 M HCl in dioxane (2 mL). After stirring for 18 hat RT, the reaction solution was adsorbed onto silica and purified viacolumn chromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding thetitle compound.

The above compound was dissolved in MeOH (2 mL), treated with excess 2MHCl in Et₂O (150 μL) and concentrated affording the HCl salt of thetitle compound: LC-MS (ES) m/z 338 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm2.74-2.81 (m, 1H) 2.83-2.90 (m, 2H) 2.92-2.98 (m, 1H) 3.63 (s, 3H) 3.76(s, 3H) 4.29 (ddd, J=8.02, 5.12, 2.53 Hz, 1H) 6.27 (d, J=4.04 Hz, 1H)6.39 (d, J=2.02 Hz, 1H) 6.80 (d, J=4.04 Hz, 1H) 7.20 (td, J=5.87, 2.65Hz, 1H) 7.26-7.31 (m, 4H) 7.57 (d, J=2.02 Hz, 1H).

Example 50

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamidea) 1,1-dimethylethyl(2-{[(4-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate

To a 50 mL round-bottomed flask was added4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (610 mg, 3.0 mmol),1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (748 mg, 2.99 mmol)[prepared according to the procedure of Preparation 2] and PyBrop (1.71g, 3.67 mmol) in Chloroform (15 mL). DIEA (1.8 mL, 10.3 mmol) was addedand the mixture stirred overnight at room temperature. The reactionmixture was adsorbed onto silica and purified via column chromatography(Hex/EtOAc) affording the title compound (335 mg, 26%): LC-MS (ES)m/z=438 (M+H)⁺.

b)1,1-dimethylethyl[2-({[1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl(2-{[(4-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate(313 mg, 0.717 mmol) in dioxane/H₂O (4:1, 6.25 mL) was added Cs₂CO₃ (840mg, 2.6 mmol), tetrakistriphenylphosphine Pd(0) (62 mg, 0.05 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (202 mg,1.04 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 12 h and was then partitioned between H₂O and CHCl₃. The combinedorganic fractions were dried (Na₂SO₄), concentrated under vacuum,adsorbed onto silica gel and purified via column chromatography (35%EtOAc/Hex) affording the title compound (285 mg, 91%): LC-MS (ES)m/z=438 (M+H)⁺.

c)N-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

HCl in Dioxane (4M, 2 mL) was added to a solution of1,1-dimethylethyl[2-({[1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate(285 mg, 0.65 mmol) in CHCl3/MeOH (10:1, 10 mL) affording the titlecompound as a white solid (71 mg, 0.21 mmol, 32%): LC-MS (ES) m/z 338(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.77-2.93 (m, 4H) 3.86 (s, 3H) 3.92(s, 3H) 4.29 (ddd, J=8.15, 4.74, 2.02 Hz, 1H) 6.30 (d, J=2.02 Hz, 1H)6.94 (d, J=1.77 Hz, 1H) 7.14 (d, J=1.77 Hz, 1H) 7.19 (td, J=5.56, 3.03Hz, 1H) 7.25-7.30 (m, 4H) 7.41 (d, J=1.77 Hz, 1H).

Example 51

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (232 mg, 1.11mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid. Thereaction mixture was absorbed onto silica and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound, which was further purified by Gilson reverse phasechromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA) to afford the TFA salt:LC-MS (ES) m/z 409 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.09-3.30 (m,4H) 3.97-4.00 (m, 3H) 4.62-4.72 (m, 1H) 6.48 (d, J=2.02 Hz, 1H) 7.43(ddd, J=8.08, 4.42, 4.17 Hz, 1H) 7.51-7.56 (m, 3H) 7.72 (d, J=7.83 Hz,1H) 7.89-7.93 (m, 2H).

Example 52

Preparation ofN-[2-(methylamino)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 20, except substituting 1,1-dimethylethyl(2-amino-3-phenylpropyl)methylcarbamate (0.32 g, 1.2 mmol) [fromPreparation 13] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamateand substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(220 mg, 1.06 mmol) for4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid: LC-MS(ES) m/z 355 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.41 (s, 3H) 2.81 (td,J=11.81, 7.96 Hz, 2H) 2.87-2.97 (m, 2H) 3.96 (s, 3H) 4.43-4.52 (m, 1H)6.45 (d, J=1.52 Hz, 1H) 7.16-7.23 (m, 1H) 7.25-7.30 (m, 4H) 7.50 (d,J=1.52 Hz, 1H) 7.85 (d, J=13.14 Hz, 2H).

Example 53

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting2-[2-(methylamino)-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg,0.7 mmol)[prepared according to the procedure of Preparation 6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCland substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(150 mg, 0.72 mmol) for4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid. Thereaction mixture was absorbed onto silica and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound, which was further purified by Gilson reverse phasechromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA) to afford the TFA salt:LC-MS (ES) m/z 355 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.86 (s, 3H)2.97 (dd, J=14.02, 8.72 Hz, 2H) 3.12-3.23 (m, 2H) 3.70 (m, 1H) 3.97 (s,3H) 6.47 (d, J=2.02 Hz, 1H) 7.30-7.35 (m, 1H) 7.37-7.43 (m, 5H) 7.51 (d,J=2.02 Hz, 1H) 7.88 (d, J=1.52 Hz, 1H) 7.94 (d, J=1.52 Hz, 1H).

Example 54

Preparation ofN-[1-(aminomethyl)-2-methyl-2-phenylpropyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (129 mg, 0.62mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid andsubstituting2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (0.20 g,0.58 mmol) [prepared according to the procedure of Preparation 14] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 369 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 1.36 (s, 3H)1.41 (s, 3H) 2.61 (d, J=6.82 Hz, 2H) 3.99 (s, 3H) 4.49 (t, J=6.95 Hz,1H) 6.49 (d, J=1.77 Hz, 1H) 7.23 (t, J=7.33 Hz, 1H) 7.36 (t, J=7.71 Hz,2H) 7.47-7.52 (m, 3H) 7.89 (d, J=1.26 Hz, 1H) 8.00 (d, J=1.52 Hz, 1H)).

Example 55

Preparation ofN-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (99 mg, 0.48mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid andsubstituting2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(155 mg, 0.44 mmol) [prepared according to procedure of Preparation 6]forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine.The reaction mixture was absorbed onto silica and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound, which was further purified by Gilson reverse phasechromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA) to afford the TFA salt:LC-MS (ES) m/z 411 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.05-3.28 (m,4H) 3.97 (s, 3H) 4.63-4.72 (m, 1H) 6.47 (d, J=2.02 Hz, 1H) 7.26-7.29 (m,1H) 7.34-7.37 (m, 1H) 7.49 (d, J=2.27 Hz, 1H) 7.51 (d, J=2.02 Hz, 1H)7.86 (d, J=1.52 Hz, 1H) 7.90 (d, J=1.52 Hz, 1H).

Example 56

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206mg, 0.93 mmol) [prepared according to the procedure of Preparation 9],2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(209 mg, 0.60 mmol) [prepared according to the procedure of Preparation6] and PyBrop (340 mg, 0.73 mmol) in Chloroform (15 mL). DIEA (0.81 mL,4.65 mmol) was added and the mixture stirred overnight at roomtemperature. Upon completion, the reaction mixture was adsorbed ontosilica and purified via column chromatography (25-75% EtOAc/Hex)affording the title compound (112 mg, 0.203 mmol, 22%): LC-MS (ES)m/z=553 (M+H)⁺

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(112 mg, 0.203 mmol) in Tetrahydrofuran (THF) (6 mL) and Methanol (1mL). Hydrazine (40 μL, 1.3 mmol) was added and the mixture stirredovernight at room temperature. Upon completion, the mixture was adsorbedonto silica gel and purified via column chromatography (90:10:1CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (43 mg, 0.102 mmol, 50% yield): LC-MS (ES) m/z 423 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.38 (s, 3H) 3.01 (m, 1H) 3.08 (d, J=6.57Hz, 3H) 3.76-3.83 (m, 3H) 4.47 (m, 1H) 6.37 (d, J=2.02 Hz, 1H) 7.41 (t,J=7.58 Hz, 1H) 7.50-7.57 (m, 2H) 7.57-7.63 (m, 1H) 7.68 (d, J=7.58 Hz,1H) 8.04 (d, J=9.09 Hz, 1H) 8.15 (s, 3H) 8.96 (s, 1H).

Example 57

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (222 mg, 1.07mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid andsubstituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(357 mg, 1.2 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 359 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.96-3.06 (m,4H) 3.92-3.98 (m, 3H) 4.40 (dd, J=8.08, 5.56 Hz, 1H) 6.48 (d, J=1.77 Hz,1H) 7.02 (td, J=8.46, 2.02 Hz, 1H) 7.14 (t, J=8.08 Hz, 2H) 7.26-7.35 (m,1H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.16-8.27 (m, 3H)8.34 (d, J=1.26 Hz, 1H) 9.08 (d, J=8.34 Hz, 1H).

Example 58

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (138 mg, 0.66mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid andsubstituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(196 mg, 0.66 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}1H-isoindole-1,3(2H)-dione-HCl.The reaction mixture was adsorbed onto silica and purified via columnchromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding the titlecompound, which was further purified by Gilson reverse phasechromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA) to afford the TFA salt:LC-MS (ES) m/z 359 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.80-3.03 (m,4H) 3.89-3.97 (m, 3H) 4.30-4.40 (m, 1H) 6.45 (d, J=1.77 Hz, 1H) 7.12 (t,J=8.84 Hz, 2H) 7.29 (dd, J=8.34, 5.56 Hz, 2H) 7.48 (d, J=1.77 Hz, 1H)7.92 (br. s, 3H) 7.96 (d, J=1.26 Hz, 1H) 8.02 (d, J=1.26 Hz, 1H) 8.58(d, J=8.84 Hz, 1H).

Example 59

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (189 mg, 0.91mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid andsubstituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(297 mg, 0.85 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 409 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.06 (d,J=7.07 Hz, 4H) 3.91-3.98 (m, 3H) 4.35-4.45 (m, 1H) 6.46 (d, J=1.77 Hz,1H) 7.47 (d, J=1.77 Hz, 1H) 7.49-7.57 (m, 2H) 7.58-7.63 (m, 1H) 7.69 (s,1H) 7.98 (d, J=1.52 Hz, 1H) 8.23 (s, 3H) 8.32 (d, J=1.26 Hz, 1H) 9.11(d, J=8.84 Hz, 1H).

Example 60

Preparation ofN-((1S)-2-amino-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (240 mg, 0.9mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid andsubstituting2-{(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(278 mg, 0.80 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 409 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.04 (m, 4H)3.96 (s, 3H) 4.42 (s, 1H) 6.44-6.49 (m, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.52(d, J=7.83 Hz, 2H) 7.66 (d, J=8.08 Hz, 2H) 8.01 (s, 1H) 8.05-8.32 (br.m, 3H) 8.34 (m, 1H) 8.9-9.2 (br. s, 1H).

Example 61

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[2-({[5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of1,1-dimethylethyl[3-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)propyl]carbamate(154 mg, 0.32 mmol) [prepared according to the procedure of Example 3]in Dioxane/H₂O (5:1, 3.1 mL) was added Cs₂CO₃ (415 mg, 1.27 mmol),tetrakistriphenylphosphine Pd(0) (29 mg, 0.03 mmol), and5-iodo-1-methyl-1H-1,2,4-triazole (95 mg, 0.46 mmol) [prepared accordingto the procedure of Preparation 15]. The reaction mixture was heated to85° C. in a sealed tube for 12 hours. The reaction was partitionedbetween H₂O and CHCl₃, the organic layer dried with Na₂SO₄, absorbedonto silica and purified via column chromatography (35-50%EtOAc/Hexanes) affording the title compound as a yellow solid (61 mg,28%): LC-MS (ES) m/z=521.

b)N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

HCl in Dioxane (4M, 1 mL) was added to a solution of1,1-dimethylethyl[2-({[5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(61 mg, 0.12 mmol) in CHCl₃/MeOH (10:1, 10 mL) and the mixture stirredovernight. Upon completion, the mixture was adsorbed onto silica gel andpurified via chromatography (90:10:1 CHCl₃/MeOH/NH₄OH). The neutralcompound was dissolved in MeOH (2 mL), treated with excess 2M HCl inEt₂O and concentrated affording the HCl salt of the title compound as awhite solid (30 mg, 0.09 mmol, 77%): LC-MS (ES) m/z 341 (M+H)⁺, ¹H NMR(400 MHz, MeOD) δ ppm 2.79-2.91 (m, 3H) 2.94 (t, J=5.56 Hz, 1H) 4.10 (s,3H) 4.25-4.34 (m, 1H) 7.18 (ddd, J=8.27, 5.75, 3.16 Hz, 1H) 7.24-7.29(m, 4H) 7.63 (d, J=4.04 Hz, 1H) 7.75 (d, J=4.04 Hz, 1H) 7.95 (s, 1H).

Example 62

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-imidazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[2-({[5-(1-methyl-1H-imidazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of1,1-dimethylethyl[2-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)ethyl]carbamate(72 mg, 0.15 mmol) [prepared according to the procedure of Example 3] indioxane/H₂O (5:1, 1.4 mL) was added Cs₂CO₃ (200 mg, 0.61 mmol),tetrakistriphenylphosphine Pd(0) (8.5 mg, 0.01 mmol), and5-bromo-1-methyl-1H-imidazole (64 mg, 0.40 mmol). The reaction mixturewas heated to 85° C. in a sealed tube for 12 h. Upon completion, thereaction mixture was partitioned between H₂O (25 mL) and CHCl₃. Theorganics were dried (Na₂SO₄), concentrated under vacuum, adsorbed ontosilica gel and purified via column chromatography (35-50% EtOAc/Hexanes)to give the title compound (19.6 mg, 31%) as a yellow solid: LC-MS (ES)m/z=441.

b)N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-imidazol-5-yl)-2-thiophenecarboxamide

HCl in Dioxane (4M, 1 mL) was added to a solution of1,1-dimethylethyl[2-({[5-(1-methyl-1H-imidazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(19.6 mg, 0.04 mmol) in CHCl₃/MeOH (10:1, 5 mL). Upon completion of thereaction, the mixture was adsorbed onto silica gel and purified viachromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound as a white solid (19 mg, 0.05 mmol, quant.): LC-MS (ES) m/z 341(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.77-2.83 (m, 1H) 2.85-2.91 (m, 2H)2.93-2.99 (m, 1H) 3.82 (s, 3H) 4.30 (ddd, J=8.08, 4.80, 1.77 Hz, 1H)7.15-7.31 (m, 7H) 7.69 (d, J=4.04 Hz, 1H) 7.76 (s, 1H).

Example 63

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (253mg, 0.69 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid. The reaction mixture was adsorbed onto silica and purified viacolumn chromatography (silica, 3% MeOH in DCM (1% NH₄OH)) yielding thetitle compound, which was further purified by Gilson reverse phasechromatography 5-95% H₂O (1% TFA)/MeCN (1% TFA) to afford the TFA salt:LC-MS (ES) m/z 569 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.14-3.30 (m,4H) 3.82 (s, 3H) 4.73 (dd, J=9.47, 4.67 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H)7.44-7.50 (m, 1H) 7.56-7.62 (m, 3H) 7.74 (d, J=7.83 Hz, 1H).

Example 64

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.50 mmol) for5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 488 (M+H)⁺, ¹H NMR(400 MHz, MeOD) δ ppm 3.15 (s, 2H) 3.23 (s, 2H) 3.84 (s, 3H) 4.65 (s,1H) 6.52-6.57 (m, 1H) 7.46 (s, 1H) 7.52-7.61 (m, 3H) 7.72 (s, 1H) 7.81(s, 1H).

Example 65

Preparation ofN-{(1S)-2-amino-1-[(2-chlorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(2-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl(157 mg, 0.5 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 455 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.11 (s, 1H)3.22 (s, 1H) 3.27 (s, 2H) 3.85 (s, 3H) 4.70 (s, 1H) 6.57 (s, 1H) 7.26(s, 2H) 7.41 (s, 2H) 7.66 (s, 1H) 7.88 (s, 1H).

Example 66

Preparation ofN-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a light yellow solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(2-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl(149 mg, 0.5 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 438 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.00 (s, 1H)3.09 (s, 1H) 3.15 (dd, J=3.41, 1.64 Hz, 2H) 3.83 (s, 4H) 4.58 (s, 1H)6.52 (d, J=2.02 Hz, 1H) 7.08-7.17 (m, 3H) 7.27-7.37 (m, 3H) 7.59 (d,J=2.02 Hz, 1H) 7.74 (d, J=3.54 Hz, 1H).

Example 67

Preparation ofN-[(1S)-2-amino-1-(1H-indol-3-ylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(1H-indol-3-yl)propyl]-1H-isoindole-1,3(2H)-dione-dione-HCl(160 mg, 0.5 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 459 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.15 (dt,J=10.42, 6.79 Hz, 3H) 3.27 (dd, J=4.04, 2.27 Hz, 1H) 3.84 (s, 3H) 4.63(d, J=6.82 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H) 7.05 (t, J=7.45 Hz, 1H) 7.13(t, J=7.07 Hz, 1H) 7.19 (s, 1H) 7.37 (d, J=8.08 Hz, 1H) 7.64-7.73 (m,2H) 7.77 (s, 1H).

Example 68

Preparation ofN-{(1S)-2-amino-1-[(2-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 6 except substituting 4-bromo-2-thiophenecarboxylicacid (104 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid andsubstituting2-[(2S)-2-amino-3-(2-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl(157 mg, 0.5 mmol) [prepared according to Preparation 6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 375 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.11-3.20 (m,1H) 3.22-3.31 (m, 3H) 4.23 (s, 3H) 4.75 (s, 1H) 6.96 (s, 1H) 7.18-7.26(m, 2H) 7.38 (d, J=6.06 Hz, 1H) 7.46 (d, J=4.55 Hz, 1H) 8.22 (s, 2H)8.32 (s, 1H).

Example 69

Preparation ofN-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 6, except substituting4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(2-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl(149 mg, 0.5 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 359 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.06-3.17 (m,2H) 3.25-3.31 (m, 2H) 4.18 (s, 3H) 4.59-4.67 (m, 1H) 6.88 (s, 1H)7.05-7.12 (m, 2H) 7.23-7.30 (m, 1H) 7.36-7.42 (m, 1H) 8.12 (d, J=1.01Hz, 1H) 8.17 (s, 1H) 8.21 (s, 1H).

Example 70

Preparation ofN-[2-amino-1-(1-naphthalenyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 20, except substituting1,1-dimethylethyl[2-amino-2-(1-naphthalenyl)ethyl]carbamate (143 mg, 0.5mmol) [from Preparation 16] for 1,1-dimethylethyl(3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 456 (M+H)⁺, ¹H NMR (400MHz, MeOD) δ ppm 3.60 (s, 1H) 3.72 (s, 1H) 3.84 (s, 3H) 6.33 (d, J=10.11Hz, 1H) 6.55 (s, 1H) 7.55-7.61 (m, 3H) 7.64 (d, J=8.34 Hz, 1H) 7.74 (s,1H) 7.92-7.99 (m, 2H) 8.09 (s, 1H) 8.26 (s, 1H).

Example 71

Preparation ofN-[2-amino-1-(1-naphthalenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 20, except substituting4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for4,5-dibromo-2-thiophenecarboxylic acid and substituting1,1-dimethylethyl[2-amino-2-(1-naphthalenyl)ethyl]carbamate (143 mg, 0.5mmol) [from Preparation 16] for 1,1-dimethylethyl(3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 377 (M+H)⁺, ¹H NMR (400MHz, MeOD) δ ppm 3.62 (d, J=4.04 Hz, 1H) 3.67-3.78 (m, 1H) 4.08-4.10 (m,3H) 6.35 (s, 1H) 6.73 (d, J=2.27 Hz, 1H) 7.55-7.60 (m, 2H) 7.62-7.67 (m,1H) 7.76 (d, J=7.33 Hz, 1H) 7.88 (d, J=2.53 Hz, 1H) 7.93-7.99 (m, 2H)8.10 (d, J=1.52 Hz, 1H) 8.23-8.27 (m, 2H).

Example 72

Preparation ofN-{2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 20, except substituting4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for4,5-dibromo-2-thiophenecarboxylic acid and substituting1,1-dimethylethyl {2-amino-2-[2-(trifluoromethyl)phenyl]ethyl}carbamate(152 mg, 0.5 mmol) [prepared according to the procedure of Preparation16] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES)m/z 395 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.36-3.39 (m, 1H) 3.46-3.53(m, 1H) 3.98 (s, 3H) 5.86-5.91 (m, 1H) 6.48 (s, 1H) 7.51 (d, J=2.02 Hz,1H) 7.60 (s, 1H) 7.76 (s, 1H) 7.83 (d, J=8.08 Hz, 2H) 7.94 (s, 1H) 8.05(s, 1H).

Example 73

Preparation ofN-{2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 20, except substituting 1,1-dimethylethyl{2-amino-2-[2-(trifluoromethyl)phenyl]ethyl}carbamate (152 mg, 0.5 mmol)[prepared according to the procedure of Preparation 16] for1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 474(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.37 (s, 1H) 3.65 (s, 1H) 3.89-4.00(m, 3H) 5.88 (s, 1H) 6.76 (d, J=2.27 Hz, 1H) 7.58 (s, 1H) 7.77 (d,J=9.60 Hz, 2H) 7.91-8.03 (m, 2H) 8.26 (d, J=2.27 Hz, 1H).

Example 74

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 24, except substituting NBS (194 mg, 1.09 mmol) forNCS: LC-MS (ES) m/z 418 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.03 (d,J=7.33 Hz, 2H) 3.23 (s, 2H) 3.90 (s, 3H) 4.56 (d, J=1.77 Hz, 1H)7.20-7.27 (m, 1H) 7.28-7.34 (m, 4H) 7.58 (s, 1H) 7.96 (s, 2H).

Example 75

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 25, except substituting NBS (67 mg, 0.5 mmol) forNCS: LC-MS (ES) m/z 488 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.10-3.19(m, 1H) 3.20-3.28 (m, 3H) 3.91 (s, 3H) 4.66 (dd, J=8.59, 3.03 Hz, 1H)7.39-7.47 (m, 1H) 7.51-7.58 (m, 2H) 7.59 (s, 1H) 7.72 (d, J=8.08 Hz, 1H)7.98 (s, 2H).

Example 76

Preparation ofN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a light yellow solid according to theprocedure of Example 6, except substituting4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl(158 mg, 0.5 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 395 (M+H)⁺, ¹H NMR (400 MHz, DMSO) δ ppm 2.94-3.06 (m,4H) 3.95 (s, 3H) 4.40 (d, J=6.06 Hz, 1H) 6.46 (d, J=1.77 Hz, 1H)7.00-7.10 (m, 3H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.10(s, 2H) 8.21 (s, 1H) 8.92 (d, J=8.0 Hz, 1H).

Example 77

Preparation ofN-{(1S)-2-amino-1-[(3-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 6, except substituting4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(3-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(157 mg, 0.5 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 395 (M+H)⁺, ¹H NMR (400 MHz, DMSO) δ ppm 2.92-3.04 (m,4H) 3.92-3.98 (m, 3H) 4.36 (d, J=5.56 Hz, 1H) 6.47 (s, 1H) 7.19-7.29 (m,2H) 7.29-7.35 (m, 1H) 7.37-7.42 (m, 1H) 7.47 (s, 1H) 8.17 (s, 3H)8.85-9.07 (m, 1H).

Example 78

Preparation ofN-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 6, except substituting4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(4-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(157 mg, 0.5 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z 395 (M+H)⁺, ¹H NMR (400 MHz, DMSO) δ ppm 2.92-2.97 (m,2H) 2.99-3.04 (m, 2H) 4.01 (s, 3H) 4.32-4.42 (m, 1H) 6.43-6.50 (m, 1H)7.27-7.37 (m, 4H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.21(s, 3H) 8.94-9.10 (m, 1H).

Example 79

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 6, except substituting4,5-dibromo-2-furancarboxylic acid (135 mg, 0.5 mmol) for5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 472 (M+H)⁺, ¹H NMR(400 MHz, DMSO) δ ppm 3.11 (d, J=9.85 Hz, 1H) 3.21-3.31 (m, 3H) 4.06 (s,3H) 4.70 (s, 1H) 6.87 (d, J=2.02 Hz, 1H) 7.33 (s, 1H) 7.41-7.48 (m, 1H)7.50-7.57 (m, 2H) 7.60 (d, J=2.02 Hz, 1H) 7.71 (d, J=7.83 Hz, 1H).

Example 80

Preparation ofN-(3-amino-1-phenylpropyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 20, except substituting1,1-dimethylethyl[3-(methylamino)-3-phenylpropyl]carbamate (125 mg, 0.5mmoles) [from Preparation 3] for 1,1-dimethylethyl(3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 420 (M+H)⁺, ¹H NMR (400MHz, DMSO) δ ppm 2.25-2.37 (m, 2H) 2.96 (d, J=8.08 Hz, 1H) 3.04-3.13 (m,1H) 3.84 (s, 3H) 5.22 (t, J=7.58 Hz, 1H) 6.53 (d, J=1.52 Hz, 1H) 7.35(d, J=6.57 Hz, 1H) 7.44 (dt, J=15.09, 7.48 Hz, 4H) 7.58.

Example 81 Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-5-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a suspension of NaH (60% in mineral oil, 2.2 g, 55 mmol) in THF (50mL) was added pyrazole (3.4 g, 50 mmol) in THF (10 mL) at roomtemperature. After 30 min, to above suspension was added Etl (7.75 g, 50mmol) dropwise. After the reaction was complete (20 h), the suspensionwas filtered, and the resulting solution was used directly with furtherpurification.

At 0° C., to above solution of 4-methylpyrazole (˜50 mmol) was addedn-BuLi (2.5M in hexane, 22 mL, 55 mmol). The reaction solution wasstirred for 1 hour at RT and then cooled to −78° C. [J. HeterocyclicChem. 41, 931 (2004)]. To the reaction solution was added2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.2 g, 55 mmol).After 15 min at −78° C., the reaction was allowed to warm to 0° C. over1 hour. The reaction was diluted with saturated NH₄Cl solution andextracted with DCM. The organics were dried over Na₂SO₄ and concentratedunder vacuum to afford a tan solid (9.8 g, 89%) which was used withoutfurther purification. LCMS (ES) m/z 141 (M+H)⁺ for [RB(OH)₂]; ¹H NMR(CDCl₃, 400 MHz) δ ppm 7.52 (d, J=2 Hz, 1H), 6.36 (d, J=2 Hz, 1H), 4.48(q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H), 1.36 (s, 12H)

b)1,1-dimethylethyl[2-({[5-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl(2-{[(5-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (100mg, 0.23 mmol) in dioxane/H₂O (5:1, 6 mL) was added K₂CO₃ (100 mg, 0.72mmol), tetrakistriphenylphosphine Pd(0) (30 mg, 26 μmol) and1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64mg, 0.29 mmol). The reaction mixture was heated to 70° C. in a sealedtube. After 12 h, the reaction mixture was concentrated under vacuum andpurified on silica (hex/EtOAc, 40-60%) to afford the title compound(0.074 g, 71%) as a light yellow solid: LC-MS (ES) m/z 455 (M+H)⁺.

c)N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-Dimethylethyl[2-({[5-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(74 mg, 0.16 mmol) was dissolved in DCM (2 mL) and treated with TFA (1mL). After 1 h, the solution was concentrated and neutralized throughsilica using 4% MeOH in DCM (1% NH₄OH). The title compound was furtherpurified using reverse-phase HPLC (C18 column: H₂O/CH₃CN, 40-10%)affording the bis-TFA salt of the title compound (47 mg, 50%) as a whitesolid: LCMS (ES) m/z 355 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.71(d, J=3.8 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.34-7.22 (m, 6H), 6.51 (d.J=1.8 Hz, 1H), 4.55 (m, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.22 (dd, J=3.5,13.1 Hz, 1H), 3.13 (dd, J=10.1, 13.1 Hz, 1H), 3.00 (m, 2H), and 1.42 (t,J=7.1 Hz, 3H).

Example 82 Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 1, except substituting 1,1-dimethylethyl(3-phenyl-2-{[(3,4,5-tribromo-2-thienyl)carbonyl]amino}propyl)carbamate(120 mg, 0.20 mmol) for1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate:LC-MS (ES) m/z 499 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.59 (d,J=2.0 Hz, 1H), 7.37-7.24 (m, 5H), 6.53 (d, J=2.0 Hz, 1H), 4.62 (m, 1H),3.27 (d, J=13.1, 4.3 Hz, 1H), 3.21 (dd, J=13.1, 9.4 Hz, 1H), 3.09 (dd,J=14.2, 6.1 Hz, 1H), 3.02 (dd, J=13.9, 9.1 Hz, 1H), and 1.96 (s, 3H).

Example 83N-[2-amino-1-(phenylmethyl)ethyl]-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)N-[2-amino-1-(phenylmethyl)ethyl]-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 1, except substituting1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(64.0 mg, 0.23 mmol) [from Preparation 17] for1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate,and substituting 1,1-dimethyl ethyl(2-{[(5-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (110mg, 0.25 mmol) for 1,1-dimethylethyl(2-{[(5-bromo-3-thienyl)carbonyl]amino}-2-phenylethyl)carbamate: LC-MS(ES) m/z 355 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.75 (d, J=3.8 Hz,1H), 7.40 (br s, 1H), 7.32-7.23 (m, 5H), 7.21 (d, J=3.8 Hz, 1H), 4.56(m, 1H), 3.86 (s, 3H), 3.23 (dd, J=13.1, 3.8 Hz, 1H), 3.15 (dd, J=12.9,10.1 Hz, 1H), 3.01 (m, 2H) and 2.10 (s, 3H).

Example 84N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 1, except substituting1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(77 mg, 0.23 mmol) [from Preparation 17] for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and substituting 1,1-dimethylethyl(2-{[(4,5-dibromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate(150 mg, 0.29 mmol) for1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate:LC-MS (ES) m/z 434 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.77 (s, 1H),7.43 (s, 1H), 7.35-7.23 (m, 5H), 4.55 (m, 1H), 3.72 (s, 3H), 3.23 (dd,J=3.5 Hz, 1H), 3.13 (dd, J=10.6, 13.1 Hz, 1H), 3.02-2.95 (m, 2H), and1.99 (s, 3H).

Example 85N-[2-amino-1-(phenylmethyl)ethyl]-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 1, except substituting1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(220 mg, 1.0 mmol) [from Preparation 17] for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and substituting 1,1-dimethylethyl(2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (150mg, 0.34 mmol) for1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate:LC-MS (ES) m/z=355 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 8.14-8.13 (m,3H), 7.35-7.20 (m, 5H), 4.58 (m, 1H), 4.07 (s, 3H), 3.36-3.22 (m, 2H),3.12-3.01 (m, 2H), and 2.21 (s, 3H).

Example 86N-[2-amino-1-(phenylmethyl)ethyl]-N-hydroxy-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl{2-[[(4-bromo-2-thienyl)carbonyl](hydroxy)amino]-3-phenylpropyl}carbamate

To a solution of 4-bromo-2-thiophenecarboxylic acid (1.0 g, 4.83 mmol)in DCM (10 mL) was added PyBrop (3.4 g, 7.24 mmol) and Hunig's base (2mL, 12.6 mmol). After 15 min,1,1-dimethylethyl[2-(hydroxyamino)-3-phenylpropyl]carbamate (641 mg,2.41 mmol) was added to the reaction mixture in DCM (2 mL) and stirredfor 2 h at RT. The reaction solution was concentrated to give crude1,1-dimethylethyl[2-([(4-bromo-2-thienyl)carbonyl]{[(4-bromo-2-thienyl)carbonyl]oxy}amino)-3-phenylpropyl]carbamate.LC-MS (ES) m/z=645 (M+H)⁺.

To a solution of1,1-dimethylethyl[2-([(4-bromo-2-thienyl)carbonyl]{[(4-bromo-2-thienyl)carbonyl]oxy}amino)-3-phenylpropyl]carbamatein MeOH (5 mL) was added K₂CO₃ (1.0 g, 7.3 mmol). The mixture wasstirred at RT for 2 h. The mixture was concentrated under vacuum andpurified on silica gel (EtOAc/Hexane, 30%) to give the title compound(410 mg, 37% for two steps) as an off white solid: LC-MS (ES) m/z=456(M+H)⁺.

b)1,1-dimethylethyl[2-(hydroxy{[4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl{2-[[(4-bromo-2-thienyl)carbonyl](hydroxy)amino]-3-phenylpropyl}carbamate(100 mg, 0.22 mmol) in dioxane/H₂O (5:1, 6 mL) was added K₂CO₃ (91 mg,0.66 mmol), tetrakistriphenylphosphine Pd(0) (23 mg, 0.022 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (68mg, 0.33 mmol). The reaction mixture was heated to 75° C. in a sealedtube. After 2 h, the reaction mixture was concentrated under vacuum andpurified on silica (EtOAc/Hex, 20-40%) to afford the title compound (87mg, 87%): LC-MS (ES) m/z=456 (M+H)⁺.

c)N-[2-amino-1-(phenylmethyl)ethyl]-N-hydroxy-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-Dimethylethyl[2-(hydroxy{[4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(84 mg, 0.19 mmol) was dissolved in DCM (2 mL) and treated with TFA (1mL). The reaction was stirred over 1 h, and concentrated, and purifiedby reverse-phase HPLC (C18 column: H₂O/CH₃CN, 40-10%), and concentratedto afford the bis-TFA salt of the title compound (51.2 mg, 64.8%). LC-MS(ES) m/z 357 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 8.03 (s, 1H), 7.94(d, J=1.8 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H),7.34-7.18 (m, 5H), 5.16 (m, 1H), 3.95 (s, 3H), 3.38 (dd, J=13.1, 10.6Hz, 1H), 3.17-3.11 (m, 2H), and 2.95 (dd, J=13.6, 6.6 Hz, 1H)

Example 87N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)4-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of 4-bromo-2-thiophenecarboxylic acid (80 mg, 0.39 mmol)in DCM (2 mL) at 25° C. was added bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP) (218 mg, 0.47 mmol) in oneportion, followed by addition of DIPEA (0.2 mL, 1.14 mmol). Afterstirring for 10 min, diamine2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(165 mg, 0.43 mmol) was added to above solution. After 2 h, the solutionwas concentrated and purified via column chromatography (silica, 10%MeOH in CH₃Cl) affording the title compound (206 mg, 99%) as a whitesolid: LC-MS (ES) m/z 538 (M+H)⁺.

b)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of4-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(200 mg, 0.37 mmol) in dioxane/H₂O (5:1, 6 mL) was added K₂CO₃ (0.17 g,1.23 mmol), tetrakistriphenylphosphine Pd(0) (42 mg, 0.036 mmol) and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(413 mg, 1.86 mmol) [from Preparation 17]. The reaction mixture washeated to 80° C. in a sealed tube for 2 h. The reaction solution wasconcentrated under vacuum, and purified on silica gel (10-50% EtOAc/Hex)to give the title compound (192 mg, 94%) as a white solid: LC-MS (ES)m/z 553 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(1,4-Dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(110 mg, 0.198 mmol) was dissolved in MeOH (2 mL) and was treated withNH₂NH₂ (0.5 mL, 15.93 mmol). The reaction was stirred over 10 h,concentrated and the residue in DCM (2 mL) was treated with TFA (1.0mL). After stirring for 2 h, the solvent was removed and the residue waspurified by reverse-phase HPLC (C18 column: H₂O/CH₃CN, 40-10%), andconcentrated to afford the bis-TFA salt of the title compound. Thebis-TFA salt was neutralized through a silica plug (90:9:1CHCl₃/MeOH/NH₄OH) affording the free base of the title compound. Thefree base, as a solution in MeOH, was then treated with excess 4M HCl indioxane affording the title compound (62 mg, 34.6%) as the HCl salt:LC-MS (ES) m/z 423 (M+H)⁺, ¹H NMR (d4-MeOD, 400 MHz) δ ppm 8.27 (s, 1H),8.22 (s, 1H), 8.18 (s, 1H), 7.70 (d, 7.8 Hz, 1H), 7.64 (d, J=7.6 Hz,1H), 7.51 (dd, J=7.3, 7.3 Hz, 1H), 7.41 (dd, J=7.6, 7.3 Hz, 1H), 4.69(m, 1H), 4.12 (s, 3H), 3.41-3.19 (m, 4H), and 2.24 (s, 3H).

Example 88N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 87, except substituting1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (104mg, 0.47 mmol) for1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LC-MS (ES) m/z=423 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 8.35-8.31 (m,2H), 8.21 (br s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H),7.51 (dd, J=7.3, 7.3 Hz, 1H), 7.42 (dd J=7.6, 7.3 Hz, 1H), 7.00 (m, 1H),4.70-4.61 (m, 3H), 3.40-3.17 (m, 4H), and 1.57 (t, J=6.8 Hz, 3H).

Example 89N-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-4-methyl-2-thiophenecarboxylic Acid

To a solution of 4-bromo-2-thiophenecarboxylic acid (2.07 g, 10 mmol) inDMF (5 mL) was added NCS (2.7 g, 15 mmol) in one portion. The reactionmixture was stirred at 50° C. for 10 h, and then cooled to roomtemperature. The desired product precipitated after water (5 mL) wasadded. The white solid was filtered and dried under high vacuum to give1.9 g (79%). LC-MS (ES) m/z=242 (M+H)⁺,

b) 1,1-dimethylethyl(2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate

To a solution of 5-chloro-4-methyl-2-thiophenecarboxylic acid (242 mg,1.0 mmol) and diisopropylethyl amine (2.5 mL, 14.60 mmol) in DCM (50 mL)at 25° C. was added PyBrOP (2.5 g, 5.30 mmol) in one portion. After 30min, 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (250 mg, 1.0mmol) was added at one portion. After 2 h, the solution was concentratedand purified via column chromatography (silica, 10-40% EtOAc in Hexane)affording the title compound (460 mg, 97%) as a white solid: LC-MS (ES)m/z=474 (M+H)⁺.

c)1,1-dimethylethyl[2-({[5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl(2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate(100 mg, 0.21 mmol) in THF (5 mL) was added Na₂CO₃ (2N, 0.3 mL, 0.6mmol), Pd(dppf)Cl₂ (20 mg, 24 μmol) and1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (92mg, 0.42 mmol). The reaction mixture was heated to 80° C. in a sealedtube under N₂. After 2 h, the reaction mixture was concentrated undervacuum and purified on silica (hex/EtOAc, 20-50%) to afford the titlecompound (74 mg, 72%) as a light yellow solid: LC-MS (ES) m/z 489(M+H)⁺.

d)N-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl[2-({[5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(61 mg, 0.12 mmol) was dissolved in DCM (2 mL) and treated with TFA (1mL). After 0.5 h, the solution was concentrated and neutralized throughsilica using 4% MeOH in DCM (1% NH₄OH). The title compound was furtherpurified using reverse-phase HPLC (C18 column: H₂O/CH₃CN, 40-10%)affording the bis-TFA salt of the title compound (41 mg, 53%) as a whitesolid. LC-MS (ES) m/z=389 (M+H)⁺. ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.61(d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.33-7.21 (m, 5H), 6.41 (d, J=2.0 Hz,1H), 4.52 (m, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.22 (dd, J=12.9, 3.5 Hz,1H), 3.12 (dd, J=12.6, 10.1 Hz, 1H), 2.98 (m, 2H), and 1.35 (t, J=7.1Hz, 3H).

Example 90N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 89(c), except substituting4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(150 mg, 0.26 mmol) for 1,1-dimethylethyl(2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate:LC-MS (ES) m/z 587 (M+H)⁺.

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(110 mg, 0.19 mmol) in MeOH/THF (5 mL/0.5 mL) was added hydrazine (0.5mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture wasconcentrated, and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,40-10%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissolved in water, and neutralized by ammonium hydroxide. Themixture was extracted with DCM (5 mL×3), dried over Na₂SO₄, andconcentrated to give a free base of the title compound, which wasdissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirringovernight, the reaction solution was concentrated to give the titlecompound (26 mg, 26%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H)⁺. ¹HNMR (d₄-MeOD, 400 MHz) δ ppm 8.28 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 7.70(d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.53 (dd, J=7.3, 7.6 Hz, 1H),7.43 (dd, J=7.6, 7.6 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 4.66 (m, 1H), 4.43(q, J=7.3 Hz, 2H), 3.37-3.16 (m, 4H), and 1.50 (t, J=7.3 Hz, 3H).

Example 91N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(260 mg, 0.46 mmol) in THF (5 mL) was added Na₂CO₃ (2N, 0.7 mL, 1.4mmol), Pd(dppf)Cl₂ (40 mg, 48 μmol) and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(303 mg, 1.38 mmol). The reaction mixture was heated to 75° C. in asealed tube under N₂. After 8 h, the reaction mixture was concentratedunder vacuum and purified on silica (10:1 CHCl₃/MeOH) to afford thetitle compound (196 mg, 73.4%): LC-MS (ES) m/z=587 (M+H)⁺.

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(196 mg, 0.34 mmol) in MeOH/THF (2 mL/0.5 mL) was added hydrazine (0.5mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture wasconcentrated, and purified on silica (50% MeOH in CHCl₃ (0.5% NH₄OH) togive a free base of the title compound, which was dissolved in MeOH (2mL), and treated with HCl (aq, 37%). After stirring overnight, thereaction solution was concentrated to give the title compound (107 mg,51%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H)⁺. ¹H NMR (d₄-MeOD, 400MHz) δ ppm 7.96 (s, 1H), 7.90 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60 (d,J=7.6 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 4.66 (m,1H), 3.91 (s, 3H), 3.33-3.14 (m, 4H), and 2.10 (s, 3H).

Example 92N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-2-thiophenecarboxylate (1.0 g, 4.52mmol) in dioxane/H₂O (5:1, 6 mL) was added K₂CO₃ (1.86 g, 13.5 mmol),tetrakistriphenylphosphine Pd(0) (260 mg, 0.23 mmol) and1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3g, 5.85 mmol). The reaction mixture was heated to 70° C. in a sealedtube. After 2 h, the reaction mixture was concentrated under vacuum andpurified on silica (hex/EtOAc, 20-40%) to afford methyl4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.7 g, 66%) as alight yellow solid: LC-MS (ES) m/z=237 (M+H)⁺.

To a solution of the above compound (0.5 g, 2.11 mmol) in THF (10 mL)was added NCS (0.364 g, 2.74 mmol). The reaction mixture was heated to70° C. under nitrogen. After 2 h, the reaction mixture was concentratedunder vacuum and purified on silica (Hexanes/EtOAc, 10-20%) to affordthe title compound (0.45 g, 78%) as a light yellow solid: LC-MS (ES) m/z271 (M+H)⁺.

(b)4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of methyl4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.3 g, 1.1mmol) in THF/H₂O (5 mL/0.5 mL) was added KOH (0.2 g, 3.4 mmol). Thereaction mixture was heated to 50° C. for 4 h and then concentrated anddiluted with H₂O (2 mL). The pH was adjusted to 3 with aqueous HCl. Themixture was extracted with DCM (3×5 mL) and the collected organicfractions were concentrated under vacuum to give crude4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (260 mg)which was used directly without further purification. LC-MS (ES) m/z=256(M+H)⁺.

To a solution of4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.26 g,1.0 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(0.35 g, 1.1 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C.was added PyBrOP (0.6 g, 1.2 mmol) in one portion. After 2 h, thesolution was concentrated and purified via column chromatography(silica, 20-50% EtOAc/hexane) affording the title compound (0.54 g, 91%)as a white solid: LC-MS (ES) m/z=588 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(350 mg, 0.60 mmol) was dissolved in MeOH (5 mL) and treated with NH₂NH₂(0.5 mL, 15.93 mmol). The mixture was stirred at RT overnight, andconcentrated. The residue was purified by column chromatography (silica,2-5% MeOH in CHCl₃ (0.5% NH₄OH) affording the free base of the titlecompound, which was treated with HCl(aq) in MeOH to give title compound(0.16 g, 51%) as a off white solid: LC-MS (ES) m/z=457 (M+H)⁺. ¹H NMR(d₄-MeOD, 400 MHz) δ ppm 7.97-7.94 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.61(s, 1H), 7.56-7.51 (m, 2H), 7.43 (dd, J=7.6, 7.6 Hz, 1H), 4.67 (m, 1H),4.22 (q, J=7.1 Hz, 2H), 3.36-3.12 (m, 4H), and 1.38 (t, J=7.1 Hz, 3H).

Example 93N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.45 g, 1.9 mmol)[see example 92(a)] in THF (5 mL) was added NBS (0.33 g, 2.5 mmol). Thereaction mixture was heated to 70° C. under nitrogen. After 2 h, thereaction mixture was concentrated under vacuum and purified on silica(EtOAc/hexanes, 10-30%) to afford the title compound (0.47 g, 78%).LC-MS (ES) m/z=316 (M+H)⁺.

b)4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of methyl4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.2 g, 0.63mmol) in THF/H₂O (5 mL/1 mL) was added KOH (0.15 g, 2.4 mmol). Thereaction mixture was heated to 50° C. for 10 h and then concentrated anddiluted with H₂O (2 mL). The pH was adjusted to 6 with aqueous HCl. Themixture was extracted with DCM (3×5 mL) and the collected organicfractions were concentrated under vacuum to give crude4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid, whichwas used directly without further purification. LC-MS (ES) m/z=302(M+H)⁺.

To a solution of4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid 156 mg,0.52 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(0.18 g, 0.52 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25°C. was added PyBrOP (0.29 g, 0.62 mmol) in one portion. After 2 h, thesolution was concentrated and purified via column chromatography(silica, 20-60% EtOAc/hexane) affording the title compound (0.281 g,86%). LC-MS (ES) m/z=632 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(250 mg, 0.39 mmol) was dissolved in MeOH (5 mL) and treated with NH₂NH₂(0.5 mL, 15.93 mmol). The mixture was stirred at RT overnight, andconcentrated. The residue was purified by column chromatography [silica,2-10% MeOH in CHCl₃ (0.5% NH₄OH)] affording the free base of the titlecompound, which was treated with HCl(aq) in MeOH to give the titlecompound (144 mg, 51%) as an off white solid: LC-MS (ES) m/z 502 (M+H)⁺.¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.93-7.87 (m, 2H), 7.72 (d, J=8.1 Hz,1H), 7.62 (s, 1H), 7.57-7.51 (m, 2H), 7.43 (t, J=6.6 Hz, 1H), 4.67 (m,1H), 4.25 (q, J=7.3 Hz, 2H), 3.37-3.11 (m, 4H), and 1.37 (t, J=7.1 Hz,3H).

Example 94

Preparation ofN-[2-amino-1-(phenylmethyl)ethyl]-3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Methyl 4-bromo-3-(methyloxy)-2-thiophenecarboxylate (250 mg, 0.10 mmol)[prepared according to Corral, C.; El-Ashmawy, M. B.; Lissavetzky, J.;Basilio, A.; Giraldez, A.; Eur. J. Med. Chem. Chim. Ther. 22; 1987;251-254.],5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (250 mg,1.20 mmol), Pd(PPh₃)₄ (58 mg, 49.8 μmol) and K₂CO₃ (550 mg, 3.98 mmol)in dioxane (5 mL) and H₂O (1 mL) were combined in a sealed tube. After12 h at 80° C., the reaction contents were partitioned between H₂O/DCM.The aqueous phase was washed several times with DCM and the combinedorganic fractions were dried over Na₂SO₄, concentrated and purified viacolumn chromatography (silica, 0.5% MeOH in DCM) affording the titlecompound (215 mg, 86%) as a brown residue: LCMS (ES) m/z=253 (M+H)⁺.

b)1,1-dimethylethyl[2-({[3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

i) A solution of methyl3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (215mg, 0.853 mmol) in 6N NaOH (4 mL) and THF (4 mL) was stirred in a sealedtube at 70° C. After 2 h, the solution was acidified to pH 3 using 1NHCl then extracted several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and used directly: LCMS(ES) m/z=239 (M+H)⁺.

ii) To a solution of the crude acid, 1,1-dimethylethyl(2-amino-3-phenylpropyl)carbamate (210 mg, 0.844 mmol) [from Preparation2] and diisopropylethyl amine (735 μL, 4.22 mmol) in DCM (8 mL) wasadded PyBrop (472 mg, 1.01 mmol) in one portion. After 1 h, the reactioncontents were partitioned between H₂O/DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and used directly: LCMS (ES) m/z=471 (M+H)⁺.

c)N-[2-amino-1-(phenylmethyl)ethyl]-3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[2-({[3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(crude from part b) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After30 min, the solution was concentrated with a toluene azeotrope and theresidue neutralized through a silica plug (3% MeOH in DCM (1% NH₄OH))affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4MHCl in dioxane affording the title compound (270 mg, 86%-2steps) as theHCl salt: LCMS (ES) m/z 371 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.06(br. s., 3H) 7.91 (s, 1H) 7.72 (d, J=8.59 Hz, 1H) 7.52 (d, J=1.77 Hz,1H) 7.25-7.31 (m, 4H) 7.18-7.23 (m, 1H) 6.39 (d, J=2.02 Hz, 1H) 4.52(br. s., 1H) 3.78 (s, 3H) 3.41 (s, 3H) 2.97-3.05 (m, 4H).

Example 95

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 5-chloro-2-thiophenecarboxylate

To a solution of 5-chloro-2-thiophenecarboxylic acid (20 g, 123 mmoles)in MeOH (200 mL) was added conc. H₂SO₄ (5 mL). After heating to 55° C.for 12 h, the reaction solution was concentrated and diluted with DCM(250 mL). The DCM solution was washed with aqueous NaHCO₃, then H₂O anddried over Na₂SO₄. Concentration under vacuum gave the title compound asa yellow oil (21.5 g, 99%): LCMS (ES) m/z 178 (M+H)⁺.

b) methyl 4-bromo-5-chloro-2-thiophenecarboxylate

To a 1 L round bottom flask was added aluminum chloride (11.32 g, 85mmol) and methyl 5-chloro-2-thiophenecarboxylate (10 g, 56.6 mmol)dissolved in CHCl₃ (250 mL). Br₂ (4.08 ml, 79 mmol) was added dropwiseover 10 minutes. After stirring for 6 h at 25° C., the light orangereaction solution was washed with sat NaHCO₃. The organic layer wasdried Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel [hexanes/EtOAc, 9:1] to give the product [12 g, 80%] as awhite solid. LCMS (ES) m/z 256 (M+H)⁺.

c) methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 300 mL sealed flask was added1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.14 g, 39.1 mmol), potassium carbonate (12.98 g, 94 mmol), methyl4-bromo-5-chloro-2-thiophenecarboxylate (8 g, 31.3 mmol) andbis(tri-t-butylphosphine)palladium(0) (0.40 g, 0.78 mmol) in 1,4-dioxane(50 ml) and H₂O (6 ml). After stirring for 90 min at 75° C., thereaction solution was diluted with DCM (100 mL) and washed with H₂O. Theorganic layer was dried Na₂SO₄, filtered and concentrated. The reactionresidue was purified on silica gel [hexanes/EtOAc, 2:1] to give theproduct [5.7 g, 70%] as a tan solid: LCMS (ES) m/z 258 (M+H)⁺.

d) 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a 250 mL round-bottomed flask was added methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (4.4 g,17.14 mmol) and sodium hydroxide (28.6 ml, 171 mmol) in tetrahydrofuran(THF) (50 ml) and MeOH (50 mL). The reaction solution was stirred at RTfor 12 h and then made acidic (pH˜2) with 2.5 M HCl and extracted withDCM. The organic layer was separated, dried (Na₂SO₄) and concentrated toan off-white solid (4.2 g, 94%) which was used directly without furtherpurification: LCMS (ES) m/z 243 (M+H)⁺.

e)5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 500 mL round-bottomed flask was added5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (4.2 g,17.31 mmol),2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(6.37 g, 19.04 mmol) [prepared according to the procedure of Preparation6], N,N-diisopropyl ethylamine (4.53 ml, 26.0 mmol) and Pybrop (12.05 g,26.0 mmol) in dichloromethane (DCM) (150 ml). After stirring at RT for12 h, the reaction solution was washed with H₂O (2×100 mL) and theorganic layer was dried Na₂SO₄, filtered and concentrated. The crudeproduct was added to a silica gel column and was eluted with[EtOAc/hexanes, 1:1] to give the product [7.8 g, 86%] as a white solid:LCMS (ES) m/z 524 (M+H)⁺.

f)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 250 mL round-bottomed flask was added5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(7.8 g, 14.91 mmol) and hydrazine (14.50 ml, 298 mmol) intetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT,the precipitate was filtered, the filtrate was concentrated. The crudeproduct was purified on a silica gel column [CHCl₃/MeOH/NH₄OH, 90:9:1]to give the title compound as a white solid.

The free base product was treated with 4M HCl in dioxane (15 mL). After5 min, the solution was concentrated and dried under vacuum to affordthe product (6.8 g, 95%) as an HCl salt: LCMS (ES) m/z 467 (M+H)⁺, ¹HNMR (400 MHz, CD3OD) δ ppm 7.97 (s, 2H), 7.31 (s, 1H), 7.14 (m, 2H),6.98 (m, 1H), 6.75 (s, 1H), 4.54 (m, 1H), 3.98 (s, 3H), 3.24 (m, 2H),3.04 (m, 2H).

Example 96

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

To a 500 mL flask was added methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (5 g, 19.48mmol) [from Example 95] and NCS (3.12 g, 23.37 mmol) in tetrahydrofuran(THF) (100 ml) (50 mL). After stirring for 4 h at 70° C., the yellowreaction solution was treated with 6M NaOH (32 mL, 195 mmole) andstirred an additional 2 hours. The reaction solution was diluted withH₂O (50 mL) and DCM (200 mL). The organic layer was separated and theaqueous layer made acidic with 6N HCl. The acidic aqueous solution wasextracted with DCM (3×200 mL), dried over Na₂SO₄, and concentrated togive the crude product [2.6 g, 48%] as a tan solid: LCMS (ES) m/z 277(M+H)⁺.

b)5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 500 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (6 g, 21.65 mmol),2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(7.25 g, 21.65 mmol) [prepared according to the procedure of Preparation6], N,N-diisopropyl ethylamine (5.67 ml, 32.5 mmol) and Pybrop (15.08 g,32.5 mmol) in Dichloromethane (DCM) (150 ml). After stirring at RT for12 h, the reaction solution was washed with H₂O (2×100 mL) and theorganic layer was dried Na₂SO₄, filtered and concentrated. The crudeproduct was added to a silica gel column and was eluted with[EtOAc/hexanes, 1:1] to give the product [9.0 g, 74%] as a white solid:LCMS (ES) m/z 558 (M+H)⁺.

c)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 250 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(9 g, 16.15 mmol) and hydrazine (15.69 ml, 323 mmol) in tetrahydrofuran(THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitatewas filtered, the filtrate was concentrated, and the crude product waspurified on a silica gel column [CHCl₃/MeOH/NH₄OH, 90:9:1] to give thetitle compound as a white solid.

The free base product was treated with 4M HCl in dioxane (15 mL). After5 min, the product solution was concentrated and dried under vacuum toafford the product (6.5 g, 91%) as an HCl salt: LCMS (ES) m/z 428(M+H)⁺, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.75 (s, 1H), 7.60 (s, 1H), 7.32(m, 1H) 7.14 (m, 2H), 6.98 (m, 1H), 4.54 (m, 1H), 3.78 (s, 3H), 3.24 (m,2H), 3.02 (m, 2H).

Example 97

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg,0.974 mmol)[prepared according to the procedure in Example 95] inacetonitrile (4.864 ml) and H₂O (486 μl) was added selectfluor (449 mg,1.27 mmol). The resulting solution was stirred at 70° C. in a sealedtube for 1 h after which additional selectfluor (449 mg, 1.266 mmol) wasadded in one portion. After stirring 12 h, the solution was partitionedbetween H₂O-DCM. The aqueous phase was washed several times with DCM-THFand the combined organic fractions were dried over Na₂SO₄, concentratedand purified via column chromatography (silica, 10% EtOAc in hexanes)affording methyl5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(65 mg, 0.237 mmol, 24.30% yield) as a yellow solid; LCMS (ES) m/z 274,276 (M, M+H).

b) 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

A solution of methyl5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(65 mg, 0.237 mmol) in 6N sodium hydroxide (0.39 ml, 2.37 mmol) andtetrahydrofuran (2 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (54 mg, 0.17 mmol, 72% yield) as a yellow oil; LCMS (ES) m/e 261,263 (M, M+2)⁺.

c)5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (53 mg, 0.203 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(78 mg, 0.203 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (0.18 ml, 1.02 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (95 mg, 0.203mmol) in one portion. The solution stirred at 25° C. over 12 h and wasthen partitioned between H₂O-DCM. The aqueous phase was washed severaltimes with DCM and the combined organic fractions were dried overNa₂SO₄, concentrated and purified via column chromatography (silica, 40%EtOAc in hexanes) yielding5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(106 mg, 0.129 mmol, 63.5% yield) as a clear oil; LCMS (ES) m/e 591, 593(M, M+H)⁺.

d)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(106 mg, 0.179 mmol) in tetrahydrofuran (1.095 ml) and methanol (1.095ml) at 25° C. was added hydrazine (0.056 ml, 1.79 mmol) dropwise. After48 h, the solution was concentrated, dry loaded (silica, 5% MeOH in DCM(1% NH₄OH)) and purified initially by column chromatography. The residuewas then further purified via gilson reverse phase chromatography using2%-95% mobile phase affording the TFA salt of the title compound. Thiscompound was neutralized through a plug of silica (5% MeOH in DCM (1%NH₄OH)) concentrated and transferred to the HCl salt adding excess 4MHCl in dioxane (500 ul) to the residue in MeOH (2 ml) affording the HClsalt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(17 mg, 0.029 mmol, 16.16% yield) as a white solid: LCMS (ES) m/z=461,463 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1H) 8.11 (s, 1H)7.71 (br. s., 3H) 7.66-7.70 (m, 2H) 7.54-7.61 (m, 2H) 7.41-7.44 (m, 1H)4.47 (br. s., 1H) 3.79 (s, 3H) 3.07-3.16 (m, 4H).

Example 98

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 4-bromo-5-ethyl-2-thiophenecarboxylate

To a solution of 4-bromo-5-ethyl-2-thiophenecarboxylic acid (1 g, 4.25mmol) in methanol (21.27 ml) was added sulfuric acid (0.23 mL, 4.25mmol). The resulting solution was stirred at 50° C. for 48 h. H₂O (50mL) was added and the reaction was cooled to 0° C. in an ice-bath. ThepH was adjusted to ˜12 and the aqueous phase was washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and used directly without further purification providingmethyl 4-bromo-5-ethyl-2-thiophenecarboxylate (1.060 g, 4.25 mmol, 100%yield): LCMS (ES) m/e 248, 250 (M, M+2)⁺.

b) methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (300 mg,1.204 mmol), potassium carbonate (832 mg, 6.02 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(326 mg, 1.565 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (30.8 mg, 0.060 mmol) werecombined in a sealed tube and stirred at 80° C. for 1 h. The reactioncontents were then partitioned between H₂O-DCM and the aqueous phase waswashed several times with DCM. The combined organic fractions were driedover Na₂SO₄ and concentrated affording methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (301 mg,1.204 mmol, 100% yield) as a brown oil: LCMS (ES) m/e 251 (M+H)⁺.

c) 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg,1.198 mmol) in 6N sodium hydroxide (2.397 ml, 1.198 mmol) andtetrahydrofuran (5.992 ml) was stirred at 70° C. in a sealed tube for 1h. The resulting solution was cooled and then partitioned betweenH₂O-DCM. The aqueous phase was adjusted to pH˜4 and then washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄and concentrated affording5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg,1.2 mmol, 100% yield) as a yellow oil; LCMS (ES) m/z=236 (M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg,1.2 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(461 mg, 1.2 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (1.043 ml, 5.99 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (615 mg, 1.317mmol) in one portion. The solution was stirred at 25° C. over 12 h andwas then partitioned between H₂O-DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, 50% EtOAc in hexanes) yieldingN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(486 mg, 0.86 mmol, 71.6% yield) as a clear oil: LCMS (ES) m/e 567(M+H)+.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(486 mg, 0.86 mmol) in tetrahydrofuran (2.144 ml) and methanol (2.14 ml)at 25° C. was added hydrazine (0.269 ml, 8.58 mmol) dropwise. After 12h, the solution was concentrated, dry loaded and purified via columnchromatography (silica, 5% MeOH in DCM (1% NH₄OH)). The free base wasthen converted to the HCl salt by adding excess 4M HCl in dioxane (500ul) to the residue in MeOH (2 ml) affordingN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(250 mg, 0.491 mmol, 57.2% yield)-2 HCl as a white solid: LCMS (ES)m/z=437 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=8.84 Hz, 1H)8.08 (br. s., 3H) 7.93 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.51-7.61 (m, 3H)7.39-7.46 (m, 1H) 6.34 (d, J=2.02 Hz, 1H) 4.48 (br. s., 1H) 3.77 (s, 3H)2.99-3.11 (m, 4H) 2.74 (q, J=7.49 Hz, 2H) 1.16 (t, J=7.45 Hz, 3H).

Example 99

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-methyl-2-thiophenecarboxylate (2 g, 8.51mmol)[prepared in Preparation 10], potassium carbonate (5.88 g, 42.5mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.124 g, 10.21 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (0.217 g, 0.425 mmol) in1,4-Dioxane (35.4 ml) and H₂O (7.09 ml) was stirred at 80° C. in asealed tube for 1 h. The reaction mixture was then partitioned betweenH₂O-DCM and the aqueous phase was washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (silica, 25% EtOAc in hexanes)affording methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate. Thisreaction was run in several batches (1 g, 3×2 g) which were combined forworkup and purification affording the title compound (5.5 g, 78%combined yield) as a viscous yellow oil: LCMS (ES) m/e 236 (M+H)⁺.

b) methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (580 mg,2.45 mmol) and n-bromosuccinimide (437 mg, 2.45 mmol) in tetrahydrofuran(12.300 ml) was stirred in a sealed tube for 1 h at 70° C. The solutionwas then partitioned between H₂O-DCM and the aqueous phase was washedseveral times with DCM. The combined organic fractions were dried overNa₂SO₄, concentrated then purified via column chromatography (silica,20% EtOAc in hexanes) yielding methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(600 mg, 1.90 mmol, 78% yield) as a yellow oil: LCMS (ES) m/e 314, 316(M, M+H)⁺.

c) methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(420 mg, 1.33 mmol), potassium carbonate (921 mg, 6.66 mmol),PdCl₂(dppf) (98 mg, 0.13 mmol) and trimethylboroxine (0.371 ml, 2.67mmol) in N,N-dimethylformamide (6.663 ml) was stirred at 110° C. in asealed tube for 2 h. This reaction was run in two batches (100 mg and420 mg) which were combined and partitioned between H₂O-DCM. The aqueousphase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (10-50% EtOAc in hexanes) affording methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (240mg, 58%) as a yellow oil: LCMS (ES) m/e 251 (M+H)⁺.

d) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic Acid

A solution of methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (240mg, 0.96 mmol) in 6N sodium hydroxide (3.20 ml, 19.18 mmol) andtetrahydrofuran (4.79 ml) was stirred at 70° C. in a sealed tube for 1h. The resulting solution was cooled and then partitioned betweenH₂O-DCM. The aqueous phase was adjusted to pH˜4 and then washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄and concentrated affording4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(217 mg, 0.92 mmol, 96% yield) as a yellow oil: LCMS (ES) m/e 236(M+H)⁺.

e)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a solution of methyl4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (217 mg,0.918 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(353 mg, 0.92 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (0.800 ml, 4.59 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (472 mg, 1.01mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen partitioned between H₂O-DCM. The aqueous phase was washed severaltimes with DCM and the combined organic fractions were dried overNa₂SO₄, concentrated and purified via column chromatography (silica,30-70% EtOAc in hexanes) yielding4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide(373 mg, 0.66 mmol, 71.7% yield) as a yellow foam: LCMS (ES) m/e 567(M+H)⁺.

f)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide(373 mg, 0.66 mmol) in tetrahydrofuran (1.65 ml) and methanol (1.65 ml)at 25° C. was added hydrazine (0.21 ml, 6.58 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 4M HCl in dioxane (1ml) to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide(253 mg, 0.497 mmol, 75% yield) as a yellow solid: LCMS (ES) m/z=437(M+H)⁺, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (d, J=8.59 Hz, 1H) 8.09(br. s., 3H) 7.82 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.58 (t, J=8.08 Hz,1H) 7.43 (t, J=7.33 Hz, 1H) 7.38 (s, 1H) 4.47 (br. s., 1H) 3.64 (s, 3H)2.99-3.07 (m, 4H) 2.27 (s, 3H) 1.89 (s, 3H).

Example 100

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamidea) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylicAcid

A solution of methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2mmol) [Prepared in Example 98] and N-chlorosuccinimide (160 mg, 1.2mmol) in tetrahydrofuran (6 ml) was stirred in a sealed tube for 1 h at70° C. 6N sodium hydroxide (1 ml, 5.99 mmol) was added in one portionand the solution stirred an additional 1 h. The reaction mixture wasthen partitioned between H₂O-DCM and the pH of the aqueous phase wasadjusted to 4 and washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated then purified via columnchromatography (silica, 20% EtOAC in hexanes) yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid(325 mg, 1.20 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 271, 273(M, M+2)⁺.

b)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid(200 mg, 0.74 mmol), N,N-diisopropylethylamine (0.64 ml, 3.69 mmol) and2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(284 mg, 0.74 mmol)[prepared according to Preparation 6] in DCM at 25°C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (414mg, 0.886 mmol) in one portion. The solution stirred at 25° C. for 1 hand was then partitioned between H₂O-DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, 50% EtOAc in hexanes) yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide(316 mg, 0.526 mmol, 71% yield) as a white foam: LCMS (ES) m/e 601, 603(M, M+2)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide(316 mg, 0.53 mmol) in tetrahydrofuran (1.314 ml) and methanol (1.3 ml)at 25° C. was added hydrazine (0.16 ml, 5.26 mmol) dropwise. After 12 h,the solution was concentrated, purified via column chromatography(silica, 5% MeOH in DCM (1% NH₄OH)) and converted to the HCl salt byadding excess 2M HCl in Et₂O (2 ml) to the residue in MeOH (5 ml)affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide(163 mg, 0.30 mmol, 57% yield) as a white solid: LCMS (ES) m/z=471, 473(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (br. s., 1H) 8.04 (bs,3H) 7.85 (s, 1H) 7.65-7.72 (m, 2H) 7.52-7.59 (m, 2H) 7.39-7.46 (m, 1H)4.41-4.47 (m, 1H) 3.71 (s, 3H) 2.98-3.07 (m, 4H) 2.67 (q, J=7.58 Hz, 2H)1.16 (t, J=7.58 Hz, 3H).

Example 101

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylicAcid

A solution of methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2mmol) [Prepared in Example 98] and N-bromosuccinimide (213 mg, 1.2 mmol)in Tetrahydrofuran (5.99 ml) was stirred in a sealed tube for 1 h at 70°C. Aqueous sodium hydroxide (4.0 ml, 23.97 mmol) was added in oneportion and the solution stirred an additional 1 h. The reaction mixturewas then partitioned between H₂O-DCM and the pH of the aqueous phase wasadjusted to ˜4 and washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated then purified via columnchromatography (silica, 20% EtOAC in hexanes) yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid(378 mg, 1.2 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 314, 316(M, M+2)⁺.

b)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid(200 mg, 0.57 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(181 mg, 0.57 mmol) [Prepared according to Preparation 6] andN,N-diisopropylethylamine (0.50 ml, 2.87 mmol) in Dichloromethane (4.23ml) at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (295 mg, 0.632 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 50% EtOAc in hexanes) yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide(240 mg, 0.37 mmol, 64.8% yield) as a white foam: LCMS (ES) m/e 645, 647(M, M+2)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide(240 mg, 0.37 mmol) in tetrahydrofuran (1.31 ml) and methanol (1.31 ml)at 25° C. was added hydrazine (0.12 ml, 3.72 mmol) dropwise. After 12 h,the solution was concentrated, purified via column chromatography(silica, 5% MeOH in DCM (1% NH₄OH)) and converted to the HCl salt byadding excess 4M HCl in dioxane (2 ml) to the residue in MeOH (5 ml)affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide(167 mg, 0.28 mmol, 76% yield) as a white solid: LCMS (ES) m/z=515, 517(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (dd, J=15.66, 9.09 Hz,1H) 8.02 (br. s., 3H) 7.80 (s, 1H) 7.66-7.72 (m, 2H) 7.54-7.61 (m, 2H)7.41-7.48 (m, 1H) 4.42-4.47 (m, 1H) 3.71 (s, 3H) 2.98-3.06 (m, 4H) 2.66(dd, J=7.45, 3.16 Hz, 2H) 1.15 (t, J=7.45 Hz, 3H).

Example 102

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicAcid

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.75 g,11.64 mmol) [Prepared in Example 99] and N-chlorosuccinimide (1.55 g,11.64 mmol) in tetrahydrofuran (58 ml) was stirred in a sealed tube for1 h at 70° C. Sodium hydroxide (9.70 ml, 58 mmol) was added in oneportion and the solution stirred an additional 1 h. The reaction mixturewas then partitioned between H₂O-DCM and the pH of the aqueous phase wasadjusted to 4 and washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated then purified via columnchromatography (silica, 20% EtOAc in hexanes) yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicacid (2.3 g, 8.96 mmol, 77% yield) as a yellow oil: LCMS (ES) m/e 257,259 (M, M+2)+.

b)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicacid (159 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol)and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6,except substituting3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 45% EtOAc in hexanes) yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(231 mg, 0.44 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 525, 527(M, M+2)⁺.

c)N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(231 mg, 0.44 mmol) in tetrahydrofuran (2.20 ml) and methanol (2.20 ml)at 25° C. was added hydrazine (0.14 ml, 4.40 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wasthen transferred to the HCl salt adding excess 4M HCl in dioxane (1 ml)to the residue in MeOH (2 ml) affording the HCl salt ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide(124 mg, 0.27 mmol, 60% yield) as a yellow solid: LCMS (ES) m/z=394, 396(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.51 (br. s., 1H) 7.97 (br.s., 3H) 7.86 (s, 1H) 7.70 (s, 1H) 4.24-4.26 (m, 1H) 3.71 (s, 3H)2.90-2.99 (m, 2H) 2.36 (s, 3H) 1.75-1.79 (m, 1H) 1.61 1.64 (m, 4H)1.48-1.51 (m, 1H) 1.31-1.36 (m, 2H) 1.10-1.14 (m, 2H) 0.91-0.94 (m, 2H).

Example 103

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg,1.06 mmol) [Prepared in Example 99] in 6N sodium hydroxide (1.76 ml,10.6 mmol) and tetrahydrofuran (5.290 ml) was stirred at 70° C. in asealed tube for 1 h. The resulting solution was cooled and partitionedbetween H₂O-DCM. The aqueous phase was adjusted to pH˜4 and then washedseveral times with DCM. The combined organic fractions were dried overNa₂SO₄ and concentrated affording5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (151mg, 0.68 mmol, 64% yield) as a white solid; LCMS (ES) m/z=223 (M+H)⁺.

b)N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (138mg, 0.62 mmol), N,N-diisopropylethylamine (0.541 ml, 3.10 mmol) and2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg,0.62 mmol) [Prepared according to the procedure of Preparation 6, exceptsubstituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine(5 g, 18.4 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 50% EtOAc in hexanes) yieldingN-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(285 mg, 0.581 mmol, 94% yield) as a white foam: LCMS (ES) m/e 491, 493(M, M+2)⁺.

c)N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution ofN-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(285 mg, 0.581 mmol) in tetrahydrofuran (2.905 ml) and methanol (2.91ml) at 25° C. was added hydrazine (0.18 ml, 5.81 mmol) dropwise. After12 h, the solution was concentrated, dry loaded onto silica and purifiedby column chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wasthen transferred to the HCl salt by adding excess 4M HCl in dioxane (1ml) to the residue in MeOH (2 ml) affording the HCl salt ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(173 mg, 0.40 mmol, 69% yield) as a yellow solid: LCMS (ES) m/z=360(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (d, J=8.59 Hz, 1H) 8.01(br. s., 3) 7.94 (s, 1H) 7.52 (d, J=2.02 Hz, 1H) 6.35 (d, J=1.77 Hz, 1H)4.24-4.27 (m, 1H) 3.77 (s, 3H) 2.91-2.94 (m, 2H) 2.39 (s, 3H) 1.72-1.77(m, 1H) 1.60-1.64 (m, 4H) 1.49-1.52 (m, 1H) 1.21-1.29 (m, 2H) 1.15-1.25(m, 2H) 0.89-0.94 (m, 2H).

Example 104

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150mg, 0.62 mmol) [Prepared in Example 95], N,N-diisopropylethylamine (0.54ml, 3.10 mmol) and2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg,0.62 mmol) [Prepared according to the procedure of Preparation 6, exceptsubstituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine(5 g, 18.4 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]inDCM at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 45% EtOAc in hexanes) yielding5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(168 mg, 0.33 mmol, 53% yield) as a clear oil: LCMS (ES) m/e 511, 513(M, M+2)⁺.

b)N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(168 mg, 0.33 mmol) in tetrahydrofuran (1.644 ml) and methanol (1.644ml) at 25° C. was added hydrazine (0.10 ml, 3.29 mmol) dropwise. After12 h, the solution was concentrated, dry loaded onto silica and purifiedby column chromatography (silica, 5% MeOH in DCM (1% NH₄OH)). The freebase was then transferred to the HCl salt adding excess 4M HCl indioxane (1 mL) to the residue in MeOH (2 ml) affording the HCl salt ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(79 mg, 0.17 mmol, 53% yield) as a yellow solid: LCMS (ES) m/z=380, 382(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.82 (d, J=8.59 Hz, 1H) 8.10(s, 1H) 7.99 (br. s., 3H) 7.55 (d, J=1.77 Hz, 1H) 6.48 (d, J=2.02 Hz,1H) 4.22-4.28 (m, 1H) 3.81 (s, 3H) 2.90-2.95 (m, 2H) 1.74-1.78 (m, 1H)1.62-1.65 (m, 4H) 1.48-1.51 (m, 1H) 1.37-1.39 (m, 2H) 1.09-1.13 (m, 2H)0.92-0.96 (m, 2H).

Example 105

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicAcid

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg,1.058 mmol)[prepared in Example 99] and N-bromosuccinimide (188 mg, 1.06mmol) in tetrahydrofuran (5.29 ml) was stirred in a sealed tube for 1 hat 70° C. Sodium hydroxide (3.53 ml, 21.16 mmol) was added in oneportion and the solution stirred an additional 1 h. The reaction mixturewas then partitioned between H₂O-DCM and the pH of the aqueous phase wasadjusted to 4 and washed several times with DCM. The combined organicfractions were dried over Na₂SO₄ and concentrated yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(289 mg, 0.96 mmol, 91% yield) as a yellow oil: LCMS (ES) m/e 301, 303(M, M+2)⁺.

b)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(187 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg,0.62 mmol)) [Prepared according to the procedure of Preparation 6,except substituting3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 50% EtOAc in hexanes) yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(226 mg, 0.40 mmol, 64% yield) as a white foam: LCMS (ES) m/e 569, 571(M, M+2)⁺.

c)N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(226 mg, 0.40 mmol) in tetrahydrofuran (1.98 ml) and methanol (1.98 ml)at 25° C. was added hydrazine (0.13 ml, 3.97 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography. The free base was then transferred to the HClsalt adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2ml) affording the HCl salt ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide(153 mg, 0.30 mmol, 75% yield) as a yellow solid: LCMS (ES) m/z=439, 441(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.51 (br. s., 1H) 7.96 (br.s., 3H) 7.83 (br. s., 1H) 7.70 (s, 1H) 4.21-4.25 (m, 1H) 3.94 (s, 3H)2.89-2.92 (m, 2H) 2.35 (s, 3H) 1.76-1.79 (m, 1H) 1.60-1.64 (m, 4H)1.48-1.54 (m, 1H) 1.26-1.32 (m, 2H) 1.09-1.16 (m, 2H) 0.92-0.95 (m, 1H)0.82-0.86 (m, 1H).

Example 106

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide

To a solution of5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (216 mg, 0.78 mmol)[prepared according to Example 96],N,N-diisopropylethylamine (0.68 ml, 3.90 mmol) and2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (252 mg,0.78 mmol) [Prepared according to the procedure of Preparation 6, exceptsubstituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine(5 g, 18.4 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (401 mg, 0.86 mmol) in one portion. The solutionstirred at 25° C. for 12 h and was then partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 40% EtOAc in hexanes) yielding5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide(303 mg, 0.55 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 545, 547(M, M+2)⁺.

b)N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide(303 mg, 0.55 mmol) in tetrahydrofuran (2.78 ml) and methanol (2.78 ml)at 25° C. was added hydrazine (0.17 ml, 5.55 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wasthen converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml)to the residue in MeOH (2 ml) affording the HCl salt ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(190 mg, 0.389 mmol, 70.0% yield) as a yellow solid: LCMS (ES) m/z=415,417 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (br. s., 1H) 8.06(s, 4H) 7.74 (s, 1H) 4.25 (dd, J=8.84, 4.29 Hz, 1H) 3.77 (s, 3H)2.87-2.93 (m, 2H) 1.71-1.79 (m, 1H) 1.64 (d, J=9.85 Hz, 3H) 1.54 (br.s., 1H) 1.48 (br. s., 1H) 1.37 (dd, J=13.26, 4.93 Hz, 1H) 1.14 (br. s.,1H) 1.17 (d, J=7.33 Hz, 2H) 0.93 (d, J=10.86 Hz, 1H) 0.82-0.89 (m, 1H).

Example 107

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylicAcid

A solution of5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (50 mg,0.21 mmol)[prepared in Example 95] and NBS (36.7 mg, 0.21 mmol) intetrahydrofuran (2.06 ml) was stirred in a sealed tube for 1 h at 70° C.The reaction mixture was then partitioned between H₂O-DCM and theaqueous phase was washed several times with DCM. The combined organicfractions were dried over Na₂SO₄ and concentrated yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid(82 mg, 0.16 mmol, 79% yield) as a yellow oil: LCMS (ES) m/e 257, 259(M, M+2)⁺.

b)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid(81 mg, 0.252 mmol), n,n-diisopropylethylamine (0.22 ml, 1.26 mmol) and2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (81 mg,0.25 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (141 mg, 0.302 mmol) in one portion. The solutionstirred at 25° C. for 12 h and was then partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 40% EtOAc in hexanes) yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide(47 mg, 0.080 mmol, 31.6% yield) as a clear oil: LCMS (ES) m/e 589, 591(M, M+2)⁺.

c)N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide(48 mg, 0.08 mmol) in tetrahydrofuran (0.41 ml) and methanol (0.41 ml)at 25° C. was added hydrazine (0.03 ml, 0.81 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wasthen converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml)to the residue in MeOH (2 ml) affording the HCl salt ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide(11 mg, 0.02 mmol, 24% yield) as a yellow solid: LCMS (ES) m/z=459, 461(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.73 (br. s., 1H) 7.96 (br.s., 4H) 7.74 (s, 1H) 4.21-4.26 (m, 1H) 3.77 (s, 3H) 2.92-2.99 (m, 2H)1.73-1.79 (m, 1H) 1.62-1.67 (m, 4H) 1.49-1.51 (m, 1H) 1.25 (br. s., 2H)1.06-1.13 (m, 2H) 0.95 (d, J=6.82 Hz, 1H) 0.82-0.89 (m, 1H).

Example 108

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamidea) methyl 4,5-dibromo-2-furancarboxylate

To a solution of 4,5-dibromo-2-furancarboxylic acid (5.7 g, 21.1 mmol)in methanol (106 ml) was added sulfuric acid (11.3 ml, 211 mmol). Theresulting solution stirred at 50° C. over 4 days. The reaction mixturewas partitioned between H₂O-DCM and the aqueous phase was washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and used directly without further purification providingmethyl 4,5-dibromo-2-furancarboxylate (5.5 g, 19.4 mmol, 92% yield):LCMS (ES) m/e 283 (M+H)⁺.

b) methyl 4-bromo-2-furancarboxylate

To a solution of methyl 4,5-dibromo-2-furancarboxylate (1 g, 3.52 mmol)in tetrahydrofuran (14.1 ml) at −40° C. was added isopropylmagnesiumchloride (1.85 ml, 3.70 mmol). After 2 h, H₂O (3.52 ml) was added andthe solution warmed to 25° C. The reaction mixture was then partitionedbetween H₂O-DCM and the aqueous phase was washed several times with DCM.The combined organic fractions were dried over Na₂SO₄, concentrated andpurified by column chromatography (3% EtOAc in hexanes) affording methyl4-bromo-2-furancarboxylate (470 mg, 2.04 mmol, 58% yield) as a whitesolid: LCMS (ES) m/e 204, 206 (M, M+2)⁺.

c) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol),potassium carbonate (1.58 g, 11.46 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(525 mg, 2.52 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (58.6 mg, 0.115 mmol) in1,4-Dioxane (9.5 ml) and water (1.9 ml) was stirred at 80° C. in asealed tube for 1 h. The solution was partitioned between H₂O-DCM andthe aqueous phase was washed several times with DCM. The combinedorganic fractions were dried over Na₂SO₄, concentrated and purified viacolumn chromatography (30% EtOAc in hexanes) affording methyl4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (124 mg, 0.60 mmol, 26%yield) as a white powder: LCMS (ES) m/e 206 (M+H)⁺.

d) 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic Acid

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate(124 mg, 0.60 mmol) in 6N sodium hydroxide (2.0 ml, 12.0 mmol) andtetrahydrofuran (3.0 ml) was stirred at 70° C. in a sealed tube for 2 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylicacid (54 mg, 0.28 mmol, 47% yield) as a white solid: LCMS (ES) m/e 192(M+H)⁺.

e)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (54mg, 0.28 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(108 mg, 0.28 mmol)[prepared in Preparation 6] andN,N-diisopropylethylamine (0.24 ml, 1.40 mmol) in DCM at 25° C. wasadded bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (158 mg,0.34 mmol) in one portion. The solution stirred at 25° C. for 1 h andwas then partitioned between H₂O-DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, 50% EtOAc in hexanes) yieldingN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(100 mg, 0.14 mmol, 50% yield) as a white solid: LCMS (ES) m/e 523(M+H)⁺.

f)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(100 mg, 0.19 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) at 25°C. was added hydrazine (0.06 ml, 1.91 mmol) dropwise. After 12 h, thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 4M HCl in dioxane (1ml) to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(56 mg, 0.12 mmol, 62% yield) as a yellow solid: LCMS (ES) m/z=393(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.70 (d, J=9.09 Hz, 1H) 8.28 (s,1H) 8.07 (br. s., 3H) 7.69 (d, J=8.08 Hz, 1H) 7.56 (d, J=8.08 Hz, 2H)7.50 (s, 1H) 7.45 (d, J=1.77 Hz, 2H) 6.51 (d, J=1.77 Hz, 1H) 4.50-4.57(m, 1H) 3.93 (s, 3H) 3.02-3.16 (m, 4H).

Example 109

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea) methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(200 mg, 0.64 mmol)[prepared in Example 99], potassium carbonate (438mg, 3.17 mmol), bis(tri-t-butylphosphine)palladium(0) (324 mg, 0.64mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (77 mg, 0.32mmol) in 1,4-dioxane (5.3 ml) and H₂O (1 ml) was stirred at 80° C. in asealed tube for 12 h. The reaction contents were partitioned betweenH₂O-DCM and the aqueous phase was washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (10-50% EtOAc in hexanes) affordingmethyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(135 mg, 0.515 mmol, 81% yield) as a yellow oil: LCMS (ES) m/z=250(M+H)⁺.

b) methyl4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

To a solution of methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(135 mg, 0.52 mmol) in methanol (2.6 ml) was added Pd—C (21.9 mg, 0.21mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h.The solution was then purged with N₂, filtered through Celite andconcentrated affording methyl4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(145 mg, 0.51 mmol, 99% yield) as a yellow oil which was used withoutfurther purification: LCMS (ES) m/e 265 (M+H)⁺.

c) 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicAcid

A solution of methyl4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(145 mg, 0.55 mmol) in 6N sodium hydroxide (1.8 ml, 10.97 mmol) andtetrahydrofuran (4.8 ml) was stirred at 60° C. in a sealed tube for 12h. The resulting solution was cooled and then partitioned betweenH₂O-DCM. The aqueous phase was adjusted to pH˜4 and then washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄and concentrated affording4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(137 mg, 0.55 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 250(M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(137 mg, 0.55 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(211 mg, 0.55 mmol)[prepared in Preparation 6] and diisopropylethylamine(0.48 ml, 2.74 mmol) in Dichloromethane (5.47 ml) at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (281 mg, 0.60mmol) in one portion. The solution stirred at 25° C. for 1 h and wasthen partitioned between H₂O-DCM. The aqueous phase was washed severaltimes with DCM and the combined organic fractions were dried overNa₂SO₄, concentrated and purified via column chromatography (silica,40-70% EtOAc in hexanes) yieldingN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide(262 mg, 0.45 mmol, 82% yield) as a clear oil: LCMS (ES) m/e 581 (M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide(262 mg, 0.45 mmol) in tetrahydrofuran (2.256 ml) and methanol (2.256ml) at 25° C. was added hydrazine (0.14 ml, 4.51 mmol) dropwise. After12 h, the solution was concentrated, dry loaded onto silica and purifiedby column chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wasconverted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml)to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide(170 mg, 0.32 mmol, 72% yield) as a yellow solid: LCMS (ES) m/z=451(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.72 (br. s., 1H) 8.05 (br. s.,2H) 7.76 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.49-7.52 (m, 2H) 7.40-7.45 (m,2H) 4.42-4.47 (m, 1H) 3.61 (br. s., 3H) 3.01-3.07 (m, 4H) 2.52-2.59 (m,2H) 2.26 (s, 3H) 1.02-1.09 (m, 3H).

Example 110

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamidea) methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (980 mg,3.92 mmol)[prepared in Example 98] and N-bromosuccinimide (697 mg, 3.92mmol) in tetrahydrofuran (19.6 ml) was stirred in a sealed tube for 1 hat 70° C. The reaction mixture was then partitioned between H₂O-DCM andthe aqueous phase was washed several times with DCM. The combinedorganic fractions were dried over Na₂SO₄, concentrated then purified viacolumn chromatography (silica, 10-40% EtOAC in hexanes) yielding methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (1.1g, 3.34 mmol, 85% yield) as a yellow oil: LCMS (ES) m/e 329, 331 (M,M+2)⁺.

b) methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (300mg, 0.911 mmol), potassium carbonate (630 mg, 4.56 mmol), PdCl₂(dppf)(66.7 mg, 0.091 mmol) and trimethylboroxin (0.25 ml, 1.82 mmol) inN,N-dimethylformamide (9.1 ml) was stirred at 110° C. in a sealed tubefor 2 h. The reaction mixture was partitioned between H₂O-DCM and theaqueous phase was washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (10-50% EtOAc in hexanes) affording methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (143 mg,0.51 mmol, 56% yield) as a yellow oil: LCMS (ES) m/z=265 (M+H)⁺.

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic Acid

A solution of methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (143 mg,0.54 mmol) in 6N sodium hydroxide (0.90 ml, 5.41 mmol) andtetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (136mg, 0.54 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 251 (M+H)⁺.

d)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[2-(trifluoromethyl)phenyl]methylethyl)-5-ethyl-2-thiophenecarboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (130mg, 0.52 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(200 mg, 0.52 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide(278 mg, 0.43 mmol, 82% yield) as a yellow oil: LCMS (ES) m/e 581(M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide(278 mg, 0.48 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at25° C. was added hydrazine (0.15 ml, 4.79 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (3-15% MeOH in DCM (1% NH₄OH)). The free base wasconverted to the HCl salt by addition of excess 2M HCl in Et₂O (1 ml) tothe residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide(196 mg, 0.36 mmol, 76% yield) as a yellow solid: LCMS (ES) m/z=451(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.86-8.93 (m, 1H) 8.15 (br. s.,3H) 7.83 (s, 1H) 7.69 (d, J=7.58 Hz, 1H) 7.55 (br. s., 1H) 7.52 (t,J=7.45 Hz, 1H) 7.42 (t, J=7.45 Hz, 1H) 7.38 (s, 1H) 4.22-4.27 (m, 1H)3.62 (s, 3H) 2.97-3.09 (m, 4H) 2.60 (q, J=7.49 Hz, 2H) 1.88 (s, 3H) 1.13(t, J=7.58 Hz, 3H).

Example 111

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamidea) methyl5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(300 mg, 0.95 mmol), potassium carbonate (658 mg, 4.76 mmol),bis(tri-t-butylphosphine)palladium(0) (24.32 mg, 0.05 mmol) and4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (0.18 ml,0.95 mmol) in 1,4-dioxane (5.3 ml) and H₂O (1.0 ml) was stirred at 80°C. in a sealed tube for 12 h. The reaction contents were partitionedbetween H₂O-DCM and the aqueous phase was washed several times with DCM.The combined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (10-50% EtOAc in hexanes) affordingmethyl5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate(171 mg, 0.58 mmol, 61% yield) as a yellow oil: LCMS (ES) m/z=276(M+H)⁺.

b) methyl5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate

To a solution of methyl5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate(171 mg, 0.62 mmol) in methanol (3 ml) was added PdOH₂ (34.8 mg, 0.25mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h.The solution was then purged with N₂, filtered through Celite andconcentrated affording methyl5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate(173 mg, 0.62 mmol, 100% yield) as a clear oil which was used withoutfurther purification: LCMS (ES) m/e 279 (M+H)⁺.

c)5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylicAcid

A solution of methyl5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate(173 mg, 0.62 mmol) in 6N sodium hydroxide (1 ml, 6.21 mmol) andtetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylicacid (148 mg, 0.49 mmol, 79% yield) as a white foam: LCMS (ES) m/e 265(M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

To a solution of5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylicacid (137 mg, 0.52 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(200 mg, 0.52 mmol) [Prepared in Preparation 6] anddiisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.572mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yieldingN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide(211 mg, 0.334 mmol, 64.2% yield) as a yellow oil: LCMS (ES) m/e 595(M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide(211 mg, 0.36 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at25° C. was added hydrazine (0.11 ml, 3.55 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wasconverted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml)to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide(108 mg, 0.20 mmol, 57% yield) as a yellow solid: LCMS (ES) m/z=465(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.71 (d, J=8.59 Hz, 1H) 8.07(br. s., 3H) 7.74 (s, 1H) 7.65-7.68 (m, 1H) 7.55-7.60 (m, 1H) 7.46-7.49(m, 1H) 7.39-7.46 (m, 2H) 4.47 (br. s., 1H) 3.57 (s, 3H) 2.99-3.05 (m,4H) 2.49-2.52 (m, 1H) 2.25 (s, 3H) 1.07-1.14 (m, 6H).

Example 112

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamidea) methyl 4-bromo-5-propyl-2-thiophenecarboxylate

To a solution of 4-bromo-5-propyl-2-thiophenecarboxylic acid (5.0 g,20.07 mmol) in methanol (100 ml) was added sulfuric acid (5.35 ml, 100mmol). The resulting solution stirred at 50° C. for 36 h. H₂O (50 mL)was added the aqueous phase was washed several times with DCM. Thecombined organic fractions were washed with saturated NaHCO₃, dried overNa₂SO₄, concentrated and used directly without further purificationproviding methyl 4-bromo-5-propyl-2-thiophenecarboxylate (5.1 g, 18.61mmol, 93% yield) as a yellow oil: LCMS (ES) m/e 262, 264 (M, M+2)⁺.

b) methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-propyl-2-thiophenecarboxylate (1.0 g,3.80 mmol), potassium carbonate (2.63 g, 19.00 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.949 g, 4.56 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (0.097 g, 0.19 mmol) were combinedin a sealed tube and stirred at 80° C. for 1 h. The reaction contentswere then partitioned between H₂O-DCM and the aqueous phase was washedseveral times with DCM. The combined organic fractions were dried overNa₂SO₄ and concentrated and purified by column chromatography (10-50%EtOAc in hexanes) affording methyl4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (1.07 g,3.76 mmol, 99% yield) as a yellow oil: LCMS (ES) m/e 265 (M+H)⁺.

c) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylicAcid

A solution of methyl4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (356 mg,1.35 mmol) and N-chlorosuccinimide (180 mg, 1.35 mmol) intetrahydrofuran (6.7 ml) was stirred in a sealed tube for 1 h at 70° C.6N sodium hydroxide (2.2 ml, 13.47 mmol) was added in one portion andthe solution stirred an additional 12 h. The reaction mixture was thenpartitioned between H₂O-DCM and the pH of the aqueous phase was adjustedto ˜4 and washed several times with DCM. The combined organic fractionswere dried over Na₂SO₄, concentrated and used directly without furtherpurification yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylicacid (357 mg, 1.25 mmol, 93% yield) as a yellow oil: LCMS (ES) m/e 271,273 (M, M+2)⁺.

d)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylicacid (148 mg, 0.52 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(200 mg, 0.52 mmol) [Prepared according to Preparation 6] anddiisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide(245 mg, 0.39 mmol, 75% yield) as a yellow oil: LCMS (ES) m/e 615, 617(M, M+2)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide(245 mg, 0.40 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at25° C. was added hydrazine (0.12 ml, 3.98 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 4M HCl in dioxane (1ml) to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide(178 mg, 0.32 mmol, 80% yield) as a yellow solid: LCMS (ES) m/z=485, 487(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.96 (br. s., 1H) 8.13 (br.s., 3H) 7.93 (s, 1H) 7.66-7.73 (m, 2H) 7.62 (br. s., 1H) 7.55 (t, J=7.45Hz, 1H) 7.42 (t, J=7.45 Hz, 1H) 4.48 (br. s., 1H) 3.71 (s, 3H) 2.99-3.08(m, 4H) 2.63 (t, J=7.20 Hz, 2H) 1.53-1.57 (m, 2H) 0.83 (t, J=7.33 Hz,3H).

Example 113

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylicAcid

A solution of methyl4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg,2.70 mmol)[prepared in Example 112] and N-bromosuccinimide (481 mg, 2.70mmol) in tetrahydrofuran (12 ml) was stirred in a sealed tube for 1 h at70° C. The reaction mixture was divided and half of the solution wastreated with 6N sodium hydroxide (2.251 ml, 13.51 mmol). The reactionmixture stirred at 70° C. in a sealed tube for 12 h and was partitionedbetween H₂O-DCM. The pH of the aqueous phase was adjusted to ˜4 andwashed several times with DCM. The combined organic fractions were driedover Na₂SO₄, concentrated and used directly affording4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid(445 mg, 1.35 mmol, 50% yield): LCMS (ES) m/e 329, 331 (M, M+2)⁺.

b)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid(171 mg, 0.52 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(200 mg, 0.52 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide(251 mg, 0.37 mmol, 72% yield) as a yellow oil: LCMS (ES) m/e 659,661(M, M+2)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide(251 mg, 0.38 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at25° C. was added hydrazine (0.12 ml, 3.81 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 4M HCl in dioxane (1ml) to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide(178 mg, 0.30 mmol, 78% yield) as a yellow solid: LCMS (ES) m/z=529, 531(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.94 (d, J=8.84 Hz, 1H) 8.10(br. s., 3H) 7.87 (d, J=1.77 Hz, 1H) 7.65-7.72 (m, 2H) 7.58 (dd,J=14.78, 7.71 Hz, 2H) 7.43 (t, J=7.45 Hz, 1H) 4.48 (br. s., 1H) 3.71 (s,3H) 2.99-3.08 (m, 4H) 2.58-2.66 (m, 2H) 1.53 (ddd, J=13.89, 6.82, 6.57Hz, 2H) 0.83 (dd, J=7.33, 2.02 Hz, 3H).

Example 114

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamidea) methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate

A solution of methyl4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg,2.70 mmol) and N-bromosuccinimide (481 mg, 2.70 mmol) in tetrahydrofuran(12 ml) was stirred in a sealed tube for 1 h at 70° C. The reactionmixture was divided and half was partitioned between H₂O-DCM. Theaqueous phase was washed several times with DCM and the combined organicfractions were dried over Na₂SO₄, concentrated and used directlyyielding methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate(464 mg, 1.35 mmol, 50% yield) as an orange oil: LCMS (ES) m/e 343, 345(M, M+2)⁺.

b) methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propylthiophene-2-carboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate(242 mg, 0.71 mmol) PdCl₂(dppf) (52 mg, 0.07 mmol), potassium carbonate(487 mg, 3.53 mmol) and trimethylboroxine (0.20 ml, 1.41 mmol) inN,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tubefor 2 h. The reaction mixture was partitioned between H₂O-DCM and theaqueous phase was washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (10-50% EtOAc in hexanes) affording methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (184mg, 0.60 mmol, 84% yield) as a yellow oil: LCMS (ES) m/z=279 (M+H)⁺.

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propylthiophene-2-carboxylic Acid

A solution of methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (0.184g, 0.66 mmol) in 6N sodium hydroxide (2.2 ml, 13.22 mmol) andtetrahydrofuran (6.6 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid(180 mg, 0.66 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 265(M+H)⁺.

d)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[2-(trifluoromethyl)benzyl]ethyl}-5-propylthiophene-2-carboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid(180 mg, 0.68 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(262 mg, 0.68 mmol)[prepared in Preparation 6] and diisopropylethylamine(0.59 ml, 3.40 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (350 mg, 0.75mmol) in one portion. The solution stirred at 25° C. for 2 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide(243 mg, 0.41 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595(M+H)⁺.

e)N-{(1S)-2-amino-1-[2-(trifluoromethyl)benzyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propylthiophene-2-carboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide(243 mg, 0.41 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) at 25°C. was added hydrazine (0.13 ml, 4.09 mmol) dropwise. After 12 h, thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base was convertedto the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to theresidue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide(172 mg, 0.30 mmol, 74% yield) as a yellow solid: LCMS (ES) m/z=465(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80 (br. s., 1H) 8.08 (br. s.,3H) 7.78 (s, 1H) 7.69 (d, J=7.58 Hz, 1H) 7.50-7.55 (m, 2H) 7.43 (t,J=7.71 Hz, 1H) 7.37 (s, 1H) 4.49 (d, J=10.36 Hz, 1H) 3.61 (s, 3H)2.99-3.06 (m, 4H) 2.54-2.59 (m, 2H) 1.87 (s, 3H) 1.48-1.55 (m, 2H) 0.81(t, J=7.33 Hz, 3H).

Example 115

Preparation ofN-{(1S)-2-amino-1-[2-(trifluoromethyl)benzyl]ethyl}-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)thiophene-2-carboxamidea) methyl5-methyl-4-{1-methyl-4-[(1E)-prop-1-en-1-yl]-1H-pyrazol-5-yl}thiophene-2-carboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(320 mg, 1.015 mmol)[prepared in Example 99], potassium carbonate (702mg, 5.08 mmol), bis(tri-t-butylphosphine)palladium(0) (25.9 mg, 0.05mmol) and (1Z)-1-propen-1-ylboronic acid (87 mg, 1.01 mmol) in1,4-dioxane (5.3 ml) and water (1.3 ml) was stirred at 80° C. in asealed tube for 12 h. The reaction contents were partitioned betweenH₂O-DCM and the aqueous phase was washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (10-50% EtOAc in hexanes) affordingmethyl5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate(243 mg, 0.88 mmol, 87% yield) as a yellow oil: LCMS (ES) m/z=277(M+H)⁺.

b) methyl5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate(243 mg, 0.88 mmol) in methanol (6.8 ml) was added Pd(OH)₂ (49 mg, 0.35mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h.The solution was then purged with N₂, filtered through Celite andconcentrated affording methyl5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(217 mg, 0.69 mmol, 78% yield) as a clear oil which was used withoutfurther purification: LCMS (ES) m/e 279 (M+H)⁺.

c) 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

A solution of methyl5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(217 mg, 0.78 mmol) in 6N sodium hydroxide (2.60 ml, 15.59 mmol) andtetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (242 mg, 0.78 mmol, 100% yield) as a white foam: LCMS (ES) m/e 265(M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (206 mg, 0.78 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(300 mg, 0.78 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (0.68 ml, 3.90 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (400 mg, 0.86mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yieldingN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(283 mg, 0.46 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595(M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(283 mg, 0.48 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at25° C. was added hydrazine (0.15 ml, 4.76 mmol) dropwise. After 12 h,the solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wasconverted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml)to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(186 mg, 0.35 mmol, 73% yield) as a yellow solid: LCMS (ES) m/z=465(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.81 (br. s., 1H) 8.13 (br. s.,3H) 7.79 (s, 1H) 7.68 (d, J=7.58 Hz, 1H) 7.59 (d, J=7.07 Hz, 1H)7.42-7.51 (m, 1H) 7.38-7.45 (m, 2H) 4.47 (br. s., 1H) 3.61 (d, J=2.78Hz, 3H) 2.99-3.08 (m, 4H) 2.25 (s, 3H) 2.11-2.21 (m, 2H) 1.41-1.48 (m,2H) 0.83 (br. s., 3H).

Example 116

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamidea) methyl 4-bromo-5-methyl-2-furancarboxylate

To a solution of methyl 5-methyl-2-furancarboxylate (1.5 g, 10.70 mmol)and aluminum trichloride (2.14 g, 16.06 mmol) in chloroform (21 ml) at0° C. was added bromine (0.77 ml, 14.99 mmol). The resulting solutionstirred at 0° C. and warmed to RT over 12 h. This reaction was run inbatches (1.5 g and 1 g) and the batches were combined, added to ice andpartitioned between H₂O-DCM. The aqueous phase was washed several timeswith DCM and the combined organic fractions were dried over Na₂SO₄,concentrated and purified by column chromatography (0.5-10% EtOAc inhexanes) affording the title compound (2.1 g, 54%) as a white solid;LCMS (ES) m/z=219, 221 (M, M+2)⁺.

b) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-5-methyl-2-furancarboxylate (2.1 g, 9.59mmol), potassium carbonate (6.63 g, 47.9 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.19 g, 10.55 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (0.24 g, 0.48 mmol) in 1,4-dioxane(40 ml) and water (8 ml) was stirred at 80° C. in a sealed tube for 1 h.1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.19 g, 10.55 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.245 g,0.48 mmol) were added and the reaction stirred an additional 1 h and waspartitioned between H₂O-DCM. The aqueous phase was washed several timeswith DCM and the combined organic fractions were dried over Na₂SO₄,concentrated and purified via column chromatography (10-40% EtOAc inhexanes) affording methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (1.7 g, 7.72mmol, 81% yield) as a yellow oil: LCMS (ES) m/e 221 (M+H)⁺.

c) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic Acid

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (200 mg, 0.91mmol) in 6N sodium hydroxide (2.3 ml, 13.62 mmol) and tetrahydrofuran(4.5 ml) was stirred at 70° C. in a sealed tube for 1 h. The resultingsolution was cooled and then partitioned between H₂O-DCM. The aqueousphase was adjusted to pH˜4 and then washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄ and concentratedaffording 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid(130 mg, 0.57 mmol, 63% yield) as a yellow oil: LCMS (ES) m/e 207(M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylicacid (130 mg, 0.63 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(243 mg, 0.63 mmol)[prepared in Preparation 6] and diisopropylethylamine(0.55 ml, 3.15 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (324 mg, 0.69mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yieldingN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(190 mg, 0.23 mmol, 37% yield) as a clear oil: LCMS (ES) m/e 537 (M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(190 mg, 0.35 mmol) in tetrahydrofuran (1.5 ml) and methanol (1.5 ml) at25° C. was added hydrazine (0.11 ml, 3.54 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base was convertedto the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to theresidue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(71 mg, 0.15 mmol, 42% yield) as a yellow solid: LCMS (ES) m/z 407(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, J=9.60 Hz, 1H) 8.04(br. s., 3H) 7.70 (d, J=7.83 Hz, 1H) 7.53-7.59 (m, 2H) 7.49 (d, J=1.77Hz, 1H) 7.38-7.45 (m, 2H) 6.33 (br. s., 1H) 4.52 (br. s., 1H) 3.80 (s,3H) 2.98-3.09 (m, 4H) 2.38 (s, 3H).

Example 117

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic Acid

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72mmol)[prepared in Example 116] and n-bromosuccinimide (485 mg, 2.72mmol) in tetrahydrofuran (13.6 ml) was stirred in a sealed tube for 1 hat 70° C. The reaction mixture was divided and half of the solution wastreated with 6N sodium hydroxide (4.54 ml, 27.2 mmol) which stirred at70° C. in a sealed tube for 4 h. The solution was partitioned betweenH₂O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washedseveral times with DCM. The combined organic fractions were dried overNa₂SO₄, concentrated and used directly affording4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(369 mg, 1.29 mmol, 48% yield) as an orange oil: LCMS (ES) m/e 285, 287(M, M+2)⁺.

b)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(200 mg, 0.70 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(270 mg, 0.70 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (0.61 ml, 3.51 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (361 mg, 0.77mmol) in one portion. The solution stirred at 25° C. for 1 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide(232 mg, 0.32 mmol, 46% yield) as a clear oil: LCMS (ES) m/e 615, 617(M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide(232 mg, 0.38 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) at 25°C. was added hydrazine (0.12 ml, 3.77 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base was convertedto the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to theresidue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide(106 mg, 0.19 mmol, 50% yield) as a yellow solid: LCMS (ES) m/z=485, 487(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, J=9.60 Hz, 1H) 7.99(br. s., 3H) 7.68 (s, 2H) 7.71 (d, J=8.08 Hz, 1H) 7.59 (d, J=7.33 Hz,1H) 7.44-7.56 (m, 1H) 7.25-7.33 (m, 1H) 4.50-4.57 (m, 1H) 3.74 (s, 3H)2.99-3.07 (m, 4H) 2.32 (s, 3H).

Example 118

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic Acid

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.36mmol) and N-chlorosuccinimide (182 mg, 1.36 mmol) in tetrahydrofuran(6.7 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodiumhydroxide (3.4 ml, 20.4 mmol) was added in one portion and the solutionstirred an additional 12 h. The reaction mixture was then partitionedbetween H₂O-DCM and the pH of the aqueous phase was adjusted to ˜4 andwashed several times with DCM. The combined organic fractions were driedover Na₂SO₄, concentrated and used directly without further purificationyielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(275 mg, 1.14 mmol, 84% yield) as a orange oil: LCMS (ES) m/e 241, 243(M, M+2)⁺.

b)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(200 mg, 0.83 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(320 mg, 0.83 mmol)[prepared according to Preparation 6] anddiisopropylethylamine (0.72 ml, 4.16 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (427 mg, 0.91mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen dry loaded onto silica and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide(246 mg, 0.40 mmol, 49% yield) as a clear oil: LCMS (ES) m/e 571, 573(M, M+2)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide(246 mg, 0.43 mmol) in tetrahydrofuran (2.1 ml) and methanol (2.1 ml) at25° C. was added hydrazine (135 μl, 4.31 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base was convertedto the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to theresidue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide(125 mg, 0.24 mmol, 56% yield) as a yellow solid: LCMS (ES) m/z=441, 443(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.63 (d, J=9.09 Hz, 1H) 8.04(br. s., 3H) 7.65-7.72 (m, 2H) 7.59 (d, J=7.33 Hz, 1H) 7.57 (br. s., 1H)7.39-7.47 (m, 1H) 7.29-7.37 (m, 1H) 4.54 (br. s., 1H) 3.73 (s, 3H)2.98-3.09 (m, 4H) 2.33 (s, 3H).

Example 119

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea) methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72mmol)[prepared in Example 116] and N-bromosuccinimide (485 mg, 2.72mmol) in tetrahydrofuran (13 ml) was stirred in a sealed tube for 1 h at70° C. The reaction mixture was divided and half of the solution waspartitioned between H₂O-DCM and the aqueous phase was washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and purified by column chromatography (5-15% EtOAc inhexanes yielding methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130mg, 0.41 mmol, 15% yield) as an orange oil: LCMS (ES) m/e 299, 301 (M,M+2)⁺.

b) methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130mg, 0.43 mmol), potassium carbonate (300 mg, 2.17 mmol), PdCl₂(dppf)(15.9 mg, 0.02 mmol) and trimethylboroxine (0.12 ml, 0.87 mmol) inN,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tubefor 2 h. The reaction mixture was partitioned between H₂O-DCM and theaqueous phase was washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (10-50% EtOAc in hexanes) affording methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg,0.26 mmol, 59% yield) as a yellow oil: LCMS (ES) m/z=235 (M+H)⁺.

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic Acid

A solution of methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg,0.26 mmol) in 6N sodium hydroxide (0.8 ml, 5.1 mmol) and tetrahydrofuran(2.5 ml) was stirred at 70° C. in a sealed tube for 1 h. The resultingsolution was cooled and then partitioned between H₂O-DCM. The aqueousphase was adjusted to pH˜4 and then washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄ and concentratedaffording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylicacid (53 mg, 0.24 mmol, 94% yield) as a white foam: LCMS (ES) m/e 221(M+H)⁺.

d)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (53 mg,0.24 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(93 mg, 0.24 mmol)[prepared according to Preparation 6] andN,N-diisopropylethylamine (0.21 ml, 1.20 mmol) in dichloromethane (2.4ml) at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (124 mg, 0.26 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then dry loaded onto silica andpurified via column chromatography (silica, 30-70% EtOAc in hexanes)yielding4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide(113 mg, 0.21 mmol, 85% yield) as a white foam: LCMS (ES) m/e 551(M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide(113 mg, 0.21 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) at 25°C. was added hydrazine (64 μl, 2.05 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base was convertedto the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to theresidue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide(32 mg, 0.06 mmol, 32% yield) as a yellow solid: LCMS (ES) m/z=421(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, J=9.09 Hz, 1H) 8.05(br. s., 3H) 7.70 (d, J=7.58 Hz, 1H) 7.54-7.61 (m, 2H) 7.40-7.47 (m, 1H)7.35 (s, 1H) 7.27 (s, 1H) 4.54 (br. s., 1H) 3.65 (s, 3H) 2.98-3.07 (m,4H) 2.26 (s, 3H) 1.90 (s, 3H).

Example 120

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 100, except substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(155 mg, 0.46 mmol)[prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=421, 423 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.76(br. s., 1H) 8.06 (br. s., 3H) 7.85 (s, 1H) 7.69 (s, 1H) 7.28-7.36 (m,1H) 7.12 (d, J=7.07 Hz, 2H) 7.03 (dd, J=17.05, 2.15 Hz, 1H) 4.36 (br.s., 1H) 3.69 (s, 3H) 2.93-3.02 (m, 4H) 2.67 (q, J=7.33 Hz, 2H) 1.16 (t,J=7.45 Hz, 3H).

Example 121

N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example110, except substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(241 mg, 0.72 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=401 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.76 (br. S.,1H) 8.11 (br. S., 3H) 7.79 (s, 1H) 7.37 (s, 1H) 7.28-7.36 (m, 1H) 7.12(d, J=6.82 Hz, 2H) 7.03 (td, J=8.65, 1.64 Hz, 1H) 4.41-4.43 (m, 1H,obscured) 3.60 (br. S., 3H) 2.99-3.02 (m, 4H) 2.60 (q, J=7.33 Hz, 2H)1.86 (s, 3H) 1.13 (t, J=7.45 Hz, 3H).

Example 122

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example110, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(277 mg, 0.72 mmol)[prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=451 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.70 (br. s.,1H) 8.06 (br. s., 3H) 7.68-7.75 (m, 1H) 7.52 (s, 1H) 7.50-7.56 (m, 3H)7.37 (s, 1H) 4.36 (d, J=8.84 Hz, 1H) 3.58 (br. s., 3H) 2.98-3.02 (m, 4H)2.55-2.61 (m, 2H) 1.86 (s, 3H) 1.12 (t, J=7.58 Hz, 3H).

Example 123

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1 g, 3.99mmol)[prepared in Example 98] and N-bromosuccinimide (0.711 g, 3.99mmol) in tetrahydrofuran (8 ml) was stirred in a sealed tube for 1 h at70° C. The reaction mixture was partitioned between H₂O-DCM and theaqueous phase was washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and purified by columnchromatography (10-50% EtOAc in hexanes yielding methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (1.2g, 3.54 mmol, 89% yield) as an orange oil: LCMS (ES) m/e 329, 331 (M,M+2)⁺.

b) methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (300mg, 0.911 mmol), potassium carbonate (630 mg, 4.56 mmol),bis(tri-t-butylphosphine)palladium(0) (23.29 mg, 0.05 mmol) and2,4,6-trivinylcycloboroxane-pyridine complex (110 mg, 0.45 mmol) in1,4-dioxane (5 ml) and Water (1 ml) was stirred at 80° C. in a sealedtube for 2 h. The reaction contents were partitioned between H₂O-DCM andthe aqueous phase was washed several times with DCM. The combinedorganic fractions were dried over Na₂SO₄, concentrated and purified viacolumn chromatography (10-50% EtOAc in hexanes) affording methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate(187 mg, 0.66 mmol, 73% yield) as a clear oil: LCMS (ES) m/z=277 (M+H)⁺.

c) methyl5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate(187 mg, 0.68 mmol) in methanol (2.5 ml) was added Pd—C (7.20 mg, 0.07mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h.The solution was then purged with N₂, filtered through Celite andconcentrated affording methyl5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (187mg, 0.64 mmol, 95% yield) as a clear oil which was used without furtherpurification: LCMS (ES) m/e 279 (M+H)⁺.

d) 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

A solution of methyl5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (181mg, 0.65 mmol) in 6N sodium hydroxide (2.16 ml, 13.0 mmol) andtetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(175 mg, 0.65 mmol, 100% yield) as a white foam: LCMS (ES) m/e 265(M+H)⁺.

e)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(175 mg, 0.66 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(255 mg, 0.66 mmol)[prepared according to Procedure 6] andN,N-diisopropylethylamine (0.58 ml, 3.31 mmol) in Dichloromethane (4.6ml) at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (340 mg, 0.73 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then dry loaded onto silica andpurified via column chromatography (silica, 30-70% EtOAc in hexanes)yieldingN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(232 mg, 0.38 mmol, 57% yield) as a clear oil: LCMS (ES) m/e 595 (M+H)⁺.

f)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution ofN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(232 mg, 0.39 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) at 25°C. was added hydrazine (122 μl, 3.90 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 4M HCl in dioxane (1ml) to the residue in MeOH (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(176 mg, 0.38 mmol, 97% yield) as a yellow solid: LCMS (ES) m/z=529, 531(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (br. s., 1H) 7.97 (br.s., 3H) 7.65-7.73 (m, 3H) 7.57 (d, J=5.05 Hz, 2H) 7.59 (br. s., 1H) 7.44(br. s., 1H) 4.48 (br. s., 1H) 3.69 (s, 3H) 2.98-3.12 (m, 4H) 1.24 (dd,J=6.82, 2.27 Hz, 3H) 1.16 (dd, J=6.82, 2.53 Hz, 3H).

Example 124

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example123, except substituting (1Z)-1-propen-1-ylboronic acid (78 mg, 0.91mmol) for 2,4,6-trivinylcycloboroxane-pyridine complex: LCMS (ES)m/z=479 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.63 (s, 1H) 8.01 (br.s., 3H) 7.67 (s, 2H) 7.56 (d, J=5.05 Hz, 2H) 7.38-7.46 (m, 2H) 4.42-4.47(m, 1H) 3.59 (s, 3H) 2.98-3.02 (m, 4H) 2.66-2.71 (m, 2H) 1.40-1.47 (m,2H) 1.13 (t, J=7.52 Hz, 3H) 0.83 (t, J=7.26 Hz, 3H).

Example 125

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 4-bromo-2-thiophenecarboxylate

To a solution of 4-bromo-2-thiophenecarboxylic acid (25 g, 121 mmol) inmethanol (241 ml) was added sulfuric acid (32 ml, 604 mmol). Theresulting solution stirred at 50° C. over 4 d. The solution waspartitioned between H₂O-DCM and the aqueous phase was washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and used directly without further purification providingmethyl 4-bromo-2-thiophenecarboxylate (26 g, 118 mmol, 97% yield), LCMS(ES) m/e 222 (M+H)⁺.

b) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-2-thiophenecarboxylate (2.5 g, 11.31 mmol),potassium carbonate (7.81 g, 56.5 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.59 g, 12.44 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.56 mmol) in1,4-dioxane (47 ml) and water (9 ml) was stirred at 80° C. in a sealedtube for 1 h.1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.59 g, 12.44 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.289 g,0.56 mmol) were added and the reaction stirred an additional 1 h. Themixture was partitioned between H₂O-DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography (10-40%EtOAc in hexanes) affording methyl4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol,99% yield) as a yellow solid: LCMS (ES) m/e 223 (M+H)⁺.

c) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(2.5 g, 11.25 mmol) and n-bromosuccinimide (2.002 g, 11.25 mmol) intetrahydrofuran (56.2 ml) was stirred in a sealed tube for 1 h at 70° C.The reaction mixture was partitioned between H₂O-DCM and the aqueousphase was washed several times with DCM. The combined organic fractionswere dried over Na₂SO₄, concentrated and purified by columnchromatography (10-50% EtOAc in hexanes yielding methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.7 g, 8.97mmol, 80% yield) as a yellow solid: LCMS (ES) m/e 301, 303 (M, M+2)⁺.

d) methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (300mg, 0.91 mmol), potassium carbonate (630 mg, 4.56 mmol),bis(tri-t-butylphosphine)palladium(0) (23 mg, 0.05 mmol) and2,4,6-trivinylcycloboroxane-pyridine complex (110 mg, 0.46 mmol) in1,4-dioxane (5 ml) and water (1 ml) was stirred at 80° C. in a sealedtube for 2 h. The reaction contents were partitioned between H₂O-DCM andthe aqueous phase was washed several times with DCM. The combinedorganic fractions were dried over Na₂SO₄, concentrated and purified viacolumn chromatography (10-50% EtOAc in hexanes) affording methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate(187 mg, 0.66 mmol, 73% yield) as a clear oil: LCMS (ES) m/z=277 (M+H)⁺.

e) methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate(187 mg, 0.68 mmol) in methanol (2.5 ml) was added Pd—C (7.20 mg, 0.07mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h.The solution was then purged with N₂, filtered through Celite andconcentrated affording methyl5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (187mg, 0.64 mmol, 95% yield) as a clear oil which was used without furtherpurification: LCMS (ES) m/e 279 (M+H)⁺.

f) methyl4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (202 mg,0.81 mmol) and NCS (108 mg, 0.81 mmol) in N,N-dimethylformamide (4 ml)was stirred in a sealed tube for 1 h at 100° C. Additional NCS (108 mg,0.81 mmol) was added and the solution stirred 1 h. The reaction mixturewas partitioned between H₂O-DCM and the aqueous phase was washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and purified via column chromatography (2-30% EtOAc inhexanes) affording methyl4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(135 mg, 0.45 mmol, 56% yield) as a yellow oil: LCMS (ES) m/e 285(M+H)⁺.

g) 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

A solution of methyl4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(135 mg, 0.47 mmol) in 6N sodium hydroxide (1.6 ml, 9.48 mmol) andtetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 12h. The resulting solution was cooled and then partitioned betweenH₂O-DCM. The aqueous phase was adjusted to pH˜4 and then washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄and concentrated affording4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(120 mg, 0.41 mmol, 87% yield) as a white foam: LCMS (ES) m/e 270, 272(M, M+2)⁺.

h)4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(120 mg, 0.44 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(171 mg, 0.44 mmol)[prepared according to Preparation 6] andn,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in Dichloromethane (4.6ml) at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then dry loaded onto silica andpurified via column chromatography (silica, 30-70% EtOAc in hexanes)yielding4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(190 mg, 0.30 mmol, 68% yield) as a white solid: LCMS (ES) m/e 601, 603(M, M+2)⁺.

i)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(190 mg, 0.32 mmol) in tetrahydrofuran (1.58 ml) and methanol (1.58 ml)at 25° C. was added hydrazine (0.08 ml, 2.53 mmol) dropwise. After 12 hthe solution was concentrated, dry loaded onto silica and purified bycolumn chromatography (5% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 4M HCl in Ether (2 ml)to the residue in DCM (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(145 mg, 0.26 mmol, 83% yield) as a yellow solid: LCMS (ES) m/z=471, 473(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80 (br. s., 1H) 7.87-7.99(m, 6H) 7.69 (d, J=7.71 Hz, 1H)) 7.57 (d, J=7.83 Hz, 1H) 7.40-7.44 (m,1H) 4.43-4.48 (m, 1H) 3.74 (s, 3H) 2.99-3.06 (m, 4H) 2.40 (d, J=7.58 Hz,2H) 1.04 (t, J=7.58 Hz, 3H).

Example 126

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example125, except substituting (1Z)-1-propen-1-ylboronic acid (125 mg, 1.46mmol) for 2,4,6-trivinylcycloboroxane-pyridine complex: LCMS (ES)m/z=485, 487 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.94 (d, J=9.09Hz, 1H) 8.05 (s, 4H) 7.98 (s, 1H) 7.69 (d, J=7.58 Hz, 1H) 7.55-7.63 (m,1H) 7.52 (t, J=7.58 Hz, 1H) 7.42 (t, J=7.33 Hz, 1H) 4.49 (d, J=4.29 Hz,1H) 3.74 (s, 3H) 2.98-3.09 (m, 4H) 2.37 (q, J=7.07 Hz, 2H) 1.37-1.45 (m,2H) 0.80 (t, J=7.33 Hz, 3H).

Example 127

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamidea) methyl 4,5-dibromo-2-furancarboxylate

To a solution of 4,5-dibromo-2-furancarboxylic acid (25 g, 93 mmol) inmethanol (185 ml) was added sulfuric acid (24.7 ml, 463 mmol). Theresulting solution stirred at 50° C. over 12 h. The solution waspartitioned between H₂O-DCM and the aqueous phase was washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and used directly without further purification providingmethyl 4,5-dibromo-2-furancarboxylate (23.67 g, 83 mmol, 90% yield),LCMS (ES) m/e 283, 285, 287 (M, M+2, M+4)⁺.

b) methyl 4-bromo-2-furancarboxylate

To a solution of methyl 4,5-dibromo-2-furancarboxylate (3.3 g, 11.62mmol) in tetrahydrofuran (46 ml) at −40° C. was added isopropylmagnesiumchloride (6.97 ml, 13.95 mmol). After 1 h, Water (11 ml) was added andthe solution warmed to 25° C. The reaction mixture was then partitionedbetween H₂O-DCM and the aqueous phase was washed several times with DCM.The combined organic fractions were dried over Na₂SO₄, concentrated andpurified by column chromatography (3% EtOAc in hexanes) affording methyl4-bromo-2-furancarboxylate (1.4 g, 6.49 mmol, 56% yield) as a yellowsolid: LCMS (ES) m/e 205, 207 (M, M+2)⁺.

c) methyl 4-bromo-5-chloro-2-furancarboxylate

A solution of methyl 4-bromo-2-furancarboxylate (1.4 g, 6.83 mmol) andNCS (0.912 g, 6.83 mmol) in N,N-dimethylformamide (13.7 ml) was stirredin a sealed tube for 1 h at 100° C. After 1 h, the solution waspartitioned between DCM−H₂O and the aqueous phase was washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and purified via column chromatography (2-10% EtOAc inhexanes) affording methyl 4-bromo-5-chloro-2-furancarboxylate (1.348 g,5.12 mmol, 75% yield) as a white solid: LCMS (ES) m/e 238, 240, 242 (M,M+2, M+4)⁺.

d) methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.05 g, 5.05 mmol)[prepared according to Preparation 7], potassiumcarbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0)(0.117 g, 0.23 mmol) in 1,4-dioxane (19.14 ml) and water (3.83 ml) wasstirred at 80° C. in a sealed tube for 1 h. The reaction mixture waspartitioned between H₂O-DCM and the aqueous phase was washed severaltimes with DCM. The combined organic fractions were dried over Na₂SO₄,concentrated and purified via column chromatography (silica, 4-25% EtOAcin hexanes) yielding methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 2.53mmol, 55% yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2)⁺.

e) 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic Acid

A solution of methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.25mmol) in 6N sodium hydroxide (4.16 ml, 24.93 mmol) and tetrahydrofuran(5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resultingsolution was cooled and then partitioned between H₂O-DCM. The aqueousphase was adjusted to pH˜4 and then washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄ and concentratedaffording 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid(267 mg, 0.59 mmol, 47% yield) as a white foam: LCMS (ES) m/e 265(M+H)⁺.

f)5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylicacid (134 mg, 0.59 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(228 mg, 0.59 mmol)[prepared according to Preparation 6] andN,N-diisopropylethylamine (0.52 ml, 2.96 mmol) in Dichloromethane (4.6ml) at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (304 mg, 0.65 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then dry loaded onto silica andpurified via column chromatography (silica, 30-70% EtOAc in hexanes)yielding5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(202 mg, 0.33 mmol, 55.8% yield) as a yellow oil: LCMS (ES) m/e 557, 559(M, M+2)⁺.

g)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(202 mg, 0.36 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at25° C. was added hydrazine (0.08 ml, 2.54 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (2% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 2M HCl in diethylether (2 ml) to the residue in DCM (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(120 mg, 0.24 mmol, 66% yield) as a yellow solid: LCMS (ES) m/z=427, 429(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.87 (d, J=9.09 Hz, 1H) 8.11(br. s., 3H) 7.66-7.73 (m, 2H) 7.57 (t, J=7.45 Hz, 2H) 7.53 (d, J=1.52Hz, 1H) 7.44 (d, J=6.82 Hz, 1H) 6.50 (d, J=1.52 Hz, 1H) 4.43-4.51 (m,1H) 3.86 (s, 3H) 2.99-3.17 (m, 4H).

Example 128

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamidea) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic Acid

A solution of methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.25mmol)[prepared according to Example 127] and n-chlorosuccinimide (166mg, 1.25 mmol) in tetrahydrofuran (6 ml) was stirred in a sealed tubefor 1 h at 70° C. 6N sodium hydroxide (4.1 ml, 24.94 mmol) was added inone portion and the solution stirred an additional 12 h. The reactionmixture was then partitioned between H₂O-DCM and the pH of the aqueousphase was adjusted to ˜4 and washed several times with DCM. The combinedorganic fractions were dried over Na₂SO₄, concentrated and used directlywithout further purification yielding5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid(232 mg, 0.44 mmol, 36% yield) as a yellow oil: LCMS (ES) m/e 261, 263(M, M+2)⁺.

b)5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide

To a solution of5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid(116 mg, 0.44 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(171 mg, 0.44 mmol)[prepared according to Preparation 6] andn,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in dichloromethane (4.6ml) at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then dry loaded onto silica andpurified via column chromatography (silica, 30-70% EtOAc in hexanes)yielding5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide(116 mg, 0.19 mmol, 42% yield) as a yellow oil: LCMS (ES) m/e 591, 593(M, M+2)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide(116 mg, 0.20 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) at 25°C. was added hydrazine (0.04 ml, 1.37 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (2% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 2M HCl in Ether (2 ml)to the residue in DCM (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(68 mg, 0.13 mmol, 65% yield) as a yellow solid: LCMS (ES) m/z=461, 463(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80 (d, J=9.09 Hz, 1H) 8.03(br. s., 3H) 7.66-7.73 (m, 2H) 7.58-7.61 (m, 1H) 7.52-7.59 (m, 2H)7.40-7.48 (m, 1H) 4.5-4.57 (m, 1H) 3.77 (s, 3H) 2.98-3.09 (m, 4H).

Example 129

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example125, except substituting methyl 4-bromo-2-furancarboxylate (5 g, 24.39mmol) for methyl 4-bromo-2-thiophenecarboxylate: LCMS (ES) m/z=455, 457(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.75 (d, J=9.09 Hz, 1H) 8.23(s, 1H) 8.05 (br. s., 3H) 7.70 (d, J=7.83 Hz, 1H) 7.53-7.60 (m, 2H)7.42=0-7.43 (m, 2H) 4.50-4.55 (m, 1H) 3.74 (s, 3H) 2.99-3.08 (m, 4H)2.39 (q, J=7.33 Hz, 2H) 1.03 (t, J=7.45 Hz, 3H).

Example 130

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example125, except substituting trimethylboroxine (0.78 ml, 5.61 mmol) for2,4,6-trivinylcycloboroxane-pyridine complex and methyl4-bromo-2-furancarboxylate (5 g, 24.39 mmol) for methyl4-bromo-2-thiophenecarboxylate: LCMS (ES) m/z=441, 443 (M, M+2)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.71 (d, J=9.35 Hz, 1H) 8.27 (s, 1H) 8.01 (br.s., 3H) 7.70 (d, J=7.58 Hz, 1H) 7.55 (t, J=6.06 Hz, 2H) 7.40-7.47 (m,2H) 4.50-4.57 (m, 1H) 3.78 (s, 3H) 2.99-3.08 (m, 4H) 1.98 (s, 3H).

Example 131

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamidea) methyl 5-ethenyl-2-furancarboxylate

A solution of methyl 5-bromo-2-furancarboxylate (2.5 g, 12.19 mmol),potassium carbonate (8.43 g, 61.0 mmol),bis(tri-t-butylphosphine)palladium(0) (0.312 g, 0.61 mmol) and2,4,6-trivinylcycloboroxane-pyridine complex (1.47 g, 6.10 mmol) in1,4-dioxane (50 ml) and water (10 ml) was stirred at 80° C. in a sealedtube for 2 h. The reaction contents were partitioned between H₂O-DCM andthe aqueous phase was washed several times with DCM. The combinedorganic fractions were dried over Na₂SO₄, concentrated and purified viacolumn chromatography (10-50% EtOAc in hexanes) affording methyl5-ethenyl-2-furancarboxylate (1.3 g, 7.09 mmol, 58% yield) as a yellowoil: LCMS (ES) m/z=153 (M+H)⁺.

b) methyl 5-ethyl-2-furancarboxylate

To a solution of methyl 5-ethenyl-2-furancarboxylate (1.3 g, 8.54 mmol)in methanol (15 ml) was added PdOH₂ (0.240 g, 1.71 mmol). The reactionmixture was hydrogenated at 1 atm (balloon) for 1 h. The solution wasthen purged with N₂, filtered through Celite and concentrated affordingmethyl 5-ethyl-2-furancarboxylate (1.2 g, 7.16 mmol, 84% yield) as aclear oil which was used without further purification: LCMS (ES) m/e 155(M+H)⁺.

c) methyl 4-bromo-5-ethyl-2-furancarboxylate

To a solution of methyl 5-ethyl-2-furancarboxylate (1.2 g, 7.78 mmol)and aluminum trichloride (1.56 g, 11.68 mmol) in chloroform (15 ml) at25° C. was added bromine (0.56 ml, 10.90 mmol). The resulting solutionstirred at 70° C. in a sealed tube for 2 h and the solution was cooled,concentrated and purified via column chromatography (silica, 5% EtOAc inhexanes) affording methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g,3.26 mmol, 41.8% yield) as a white solid; LCMS (ES) m/z=233, 235 (M,M+2)⁺.

d) methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 4.72mmol), potassium carbonate (3.26 g, 23.60 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.178 g, 5.66 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were combinedin a sealed tube and stirred at 80° C. for 1 h. LCMS showed 4:1 pdt/sm.Additional1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.178 g, 5.66 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.121 g,0.24 mmol) were added and the solution stirred an additional 2 h wherecrude LCMS showed nearly complete conversion to product. The reactioncontents were then partitioned between H₂O-DCM and the aqueous phase waswashed several times with DCM. The combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography (10-50%EtOAc in hexanes) affording methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 3.37mmol, 71.3% yield) as a yellow oil: LCMS (ES) m/e 235 (M+H)⁺.

e) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic Acid

A solution of methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 4.06mmol) and N-chlorosuccinimide (542 mg, 4.06 mmol) in tetrahydrofuran (20ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide(13.5 ml, 81 mmol) was added in one portion and the solution stirred anadditional 1 h. The reaction mixture was then partitioned betweenH₂O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washedseveral times with DCM. The combined organic fractions were dried overNa₂SO₄, concentrated and used directly without further purificationyielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylicacid (683 mg, 2.55 mmol, 62.8% yield) as a yellow oil: LCMS (ES) m/e254, 256 (M, M+2)⁺.

f)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid(145 mg, 0.57 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(219 mg, 0.57 mmol)[prepared according to Preparation 6] andN,N-diisopropylethylamine (0.50 ml, 2.85 mmol) in dichloromethane (4.6ml) at 25° C. was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (292 mg, 0.63 mmol) in one portion. The solutionstirred at 25° C. for 1 h and was then dry loaded onto silica andpurified via column chromatography (silica, 30-70% EtOAc in hexanes)yielding4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide(250 mg, 0.41 mmol, 71% yield) as a white solid: LCMS (ES) m/e 585, 587(M, M+2)⁺.

g)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide(250 mg, 0.43 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at25° C. was added hydrazine (0.13 ml, 4.27 mmol) dropwise. After 12 h thesolution was concentrated, dry loaded onto silica and purified by columnchromatography (2% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 2M HCl in Ether (2 ml)to the residue in DCM (2 ml) affording the HCl salt ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide(166 mg, 0.30 mmol, 70% yield) as a yellow solid: LCMS (ES) m/z=455, 457(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (br. s., 1H) 8.06 (br.s., 3H) 7.67 (s, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.59 (d, J=4.29 Hz, 2H)7.44 (d, J=4.04 Hz, 1H) 7.31 (d, J=5.81 Hz, 1H) 4.50-4.57 (m, 1H) 3.72(s, 3H) 2.99-3.12 (m, 4H) 2.63 (q, J=7.33 Hz, 2H) 1.21 (t, J=7.45 Hz,3H).

Example 132

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example131, except substituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(170 mg, 0.57 mmol)[prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=405, 407(M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.56(d, J=8.59 Hz, 1H) 8.09 (br. s., 3H) 7.67 (s, 1H) 7.33 (s, 1H) 7.31 (dd,J=8.34, 5.81 Hz, 2H) 7.12 (t, J=8.72 Hz, 2H) 4.36-4.39 (m, 1H) 3.71 (s,3H) 2.91-3.03 (m, 4H) 2.62 (q, J=7.58 Hz, 2H) 1.20 (t, J=7.45 Hz, 3H).

Example 133

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example131, except substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(170 mg, 0.57 mmol)[prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=405, 407 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62(d, J=8.59 Hz, 1H) 8.13 (br. s., 3H) 7.67 (s, 1H) 7.30-7.37 (m, 2H) 7.12(d, J=6.32 Hz, 2H) 7.04 (t, J=8.59 Hz, 1H) 4.40-4.47 (m, 1H) 3.71 (s,3H) 2.95-3.09 (m, 4H) 2.62 (q, J=7.07 Hz, 2H) 1.20 (t, J=7.33 Hz, 3H).

Example 134

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to theprocedure of Example 127, except substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(295 mg, 0.88 mmol)[prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=377, 379 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.87(d, J=8.84 Hz, 1H) 8.16 (br. s., 3H) 7.70-7.77 (m, 1H) 7.53 (d, J=1.77Hz, 1H) 7.32 (t, J=7.20 Hz, 1H) 7.09-7.14 (m, 1H) 7.11 (d, J=6.57 Hz,2H) 7.04 (t, J=8.59 Hz, 1H) 6.49 (d, J=1.77 Hz, 1H) 4.41-4.44 (m, 1H)3.86 (s, 3H) 2.95-3.00 (m, 4H).

Example 135

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to theprocedure of Example 127, except substituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(295 mg, 0.88 mmol)[prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=377, 379 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80(d, J=8.84 Hz, 1H) 8.11 (br. s., 3H) 7.71 (s, 1H) 7.53 (d, J=1.77 Hz,1H) 7.29 (dd, J=8.59, 5.56 Hz, 2H) 7.12 (t, J=8.84 Hz, 2H) 6.49 (d,J=1.77 Hz, 1H) 4.32-4.38 (m, 1H) 3.86 (s, 3H) 2.99-3.01 (m, 4H).

Example 136

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to theprocedure of Example 127, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(340 mg, 0.88 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=427, 429 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.83(d, J=8.84 Hz, 1H) 8.11 (br. s., 3H) 7.62-7.69 (m, 2H) 7.51-7.59 (m, 4H)6.48 (d, J=1.77 Hz, 1H) 4.39-4.44 (m, 1H) 3.85 (s, 3H) 2.97-3.05 (m,4H).

Example 137

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to theprocedure of Example 128, except substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(321 mg, 0.96 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=411, 413 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.77(d, J=8.84 Hz, 1H) 8.04 (br. s., 3H) 7.72 (s, 1H) 7.59 (s, 1H) 7.30-7.38(m, 1H) 7.11 (d, J=7.58 Hz, 2H) 7.05 (t, J=8.59 Hz, 1H) 4.39-4.43 (m,1H) 3.77 (s, 3H) 2.97-3.03 (m, 4H).

Example 138

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to theprocedure of Example 128, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(221 mg, 0.58 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=461, 463 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.83(d, J=8.84 Hz, 1H) 8.10 (br. s., 3H) 7.72 (s, 1H) 7.64 (s, 1H) 7.52-7.60(m, 4H) 4.39-4.41 (m, 1H) 3.76 (s, 3H) 2.98-3.05 (m, 4H).

Example 139

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to theprocedure of Example 128, except substituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(256 mg, 0.77 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=411, 413 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.78(d, J=8.59 Hz, 1H) 8.06 (br. s., 3H) 7.72 (s, 1H) 7.60 (s, 1H) 7.30 (dd,J=8.59, 5.56 Hz, 2H) 7.13 (t, J=8.84 Hz, 2H) 4.35-4.42 (m, 1H) 3.77 (s,3H) 2.99 (br. s., 2H) 2.86-2.93 (m, 2H).

Example 140

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 127, except substituting1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.02 g, 4.59 mmol)[prepared according to Preparation 17] for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(132 mg, 0.39 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=391, 393 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.75(d, J=8.84 Hz, 1H) 8.04 (br. s., 3H) 7.55 (s, 1H) 7.37 (s, 1H) 7.30-7.36(m, 1H) 7.11-7.15 (m, 2H) 7.05-7.10 (m, 1H) 4.42 (br. s., 1H) 3.70 (s,3H) 2.97 (br. s., 2H) 2.92-2.96 (m, 2H) 1.94 (s, 3H).

Example 141

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 127, except substituting1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.06 g, 13.78 mmol)[prepared according to Preparation 17] for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(174 mg, 0.52 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=391, 393 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.81(d, J=8.59 Hz, 1H) 8.14 (br. s., 3H) 7.59 (s, 1H) 7.37 (s, 1H) 7.30 (dd,J=8.59, 5.56 Hz, 2H) 7.12 (t, J=8.84 Hz, 2H) 4.32-4.38 (m, 1H) 3.70 (s,3H) 2.98 (d, J=5.81 Hz, 2H) 2.91 (d, J=6.32 Hz, 2H) 1.94 (s, 3H).

Example 142

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 127, except substituting1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.06 g, 13.78 mmol)[prepared according to Preparation 17] for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(200 mg, 0.52 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=441, 443 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.83(br. s., 1H) 8.15 (br. s., 2H) 7.63 (br. s., 1H) 7.52-7.58 (m, 4H) 7.37(s, 1H) 4.38-4.42 (m, 1H) 3.68 (s, 3H) 2.97-3.08 (m, 4H) 1.93 (s, 3H).

Example 143

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 127, except substituting1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.06 g, 13.78 mmol)[prepared according to Preparation 17] for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(200 mg, 0.52 mmol) [prepared according the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LCMS (ES) m/z=441, 443 (M, M+2)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.87(d, J=9.35 Hz, 1H) 8.11 (br. s., 3H) 7.70 (d, J=7.83 Hz, 1H) 7.52-7.57(m, 3H) 7.41-7.47 (m, 1H) 7.38 (s, 1H) 4.39-4.43 (m, 1H) 3.71 (s, 3H)2.98-3.09 (m, 4H) 1.95 (s, 3H).

Example 144

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (3.30 g, 11.54mmol) in dioxane/H₂O (4:1, 100 mL) was added K₂CO₃ (5.5 g, 40.0 mmol),tetrakistriphenylphosphine Pd(0) (671 mg, 0.58 mmol) and5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (2.66 g,13.71 mmol). The reaction mixture was heated to 80° C. in a sealed tubefor 12 hours. The reaction mixture was partitioned between H₂O andCHCl₃. The pH of the aqueous phase was adjusted to ˜3 with 6N HCl andwashed several times with CHCl₃. The combined organic fractions weredried (Na₂SO₄), concentrated under vacuum and used directly withoutfurther purification (3.3 g, quant.): LC-MS (ES) m/z=289 (M+H)⁺.

b) 4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

N-chlorosuccinimide (NCS) (299 mg, 2.194 mmol) was added in portions toa 30 mL sealed tube reactor containing4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (503 mg,1.23 mmol) in tetrahydrofuran (THF) (6 mL) at room temperature. Themixture was heated to 70° C. for 2 hours. Upon completion, the reactionmixture was partitioned between CHCl₃ and H₂O, the organic layer driedwith Na₂SO₄, solvents removed by vacuum distillation affording the titlecompound (0.54 mg, quant.) which was used without further purification.LC-MS (ES) m/z=321 (M+H)⁺

c)4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(224 mg, 0.52 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(201 mg, 0.52 mmol) [prepared according to the procedure of Preparation6] and PyBrop (295 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL,2.63 mmol) was added and the mixture stirred overnight at roomtemperature. The reaction mixture was adsorbed onto silica and purifiedvia column chromatography (hexanes/EtOAc) affording the title compound(153 mg, 43%): LC-MS (ES) m/z=651 (M+H)⁺.

d)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(153 mg, 0.223 mmol) in tetrahydrofuran (THF) (2.5 mL) and Methanol (0.5mL). Hydrazine (50 μL, 1.59 mmol) was added and the mixture stirredovernight at room temperature. Upon completion, the mixture was adsorbedonto silica gel and purified via column chromatography (90:10:1CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (68 mg, 0.11 mmol, 48.7% yield): LC-MS (ES) m/z=523 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.02-3.14 (m, 4H) 3.73 (s, 3H) 4.50 (s, 1H)7.40-7.48 (m, 1H) 7.56-7.64 (m, 2H) 7.71 (d, J=7.83 Hz, 1H) 7.77 (s, 1H)8.14 (s, 3H) 8.21 (s, 1H) 9.24 (d, J=9.09 Hz, 1H).

Example 145

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

The title compound was prepared according to the procedure of Example144 except substituting N-bromosuccinimide (NBS) (287 mg, 1.596 mmol)for NCS: LC-MS (ES) m/z=364 (M+H)⁺.

b)4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(238 mg, 0.52 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(209 mg, 0.54 mmol) [prepared according to the procedure of Preparation6] and PyBrop (293 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL,2.62 mmol) was added and the mixture stirred overnight at roomtemperature. The reaction mixture was adsorbed onto silica and purifiedvia column chromatography (silica) (3:1 hex/EtOAc) affording the titlecompound (229 mg, 60%): LC-MS (ES) m/z=695 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(229 mg, 0.312 mmol) in Tetrahydrofuran (THF) (2.5 mL) and methanol (0.5mL). Hydrazine (60 μL, 1.91 mmol) was added and the mixture stirredovernight at room temperature. The reaction mixture was adsorbed ontosilica gel and purified by column chromatography (90:10:1CHCl₃/MeOH/NH₄OH; 12 g column).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O (500 mL) and concentrated affording the HCl salt of thetitle compound (104 mg, 0.15 mmol, 49% yield): LC-MS (ES) m/z=567(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.10 (s, 4H) 3.74 (s, 3H) 4.50(s, 1H) 7.45 (ddd, J=7.96, 4.17, 4.04 Hz, 1H) 7.60 (d, J=4.04 Hz, 2H)7.71 (d, J=7.58 Hz, 1H) 7.76 (s, 1H) 8.11 (s, 3H) 8.19 (s, 1H) 9.19 (d,J=8.84 Hz, 1H).

Example 146

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of 4-bromo-2-thiophenecarboxylic acid (3.91 g, 18.9 mmol)in dioxane/H₂O (4:1, 100 mL) was added Cs₂CO₃ (21.7 g, 66.6 mmol),tetrakistriphenylphosphine Pd(0) (1.1 g, 0.95 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.94 g, 18.94 mmol) [prepared according to the procedure of Preparation7]. The reaction mixture was heated to 85° C. in a sealed tube for 12hours and partitioned between H₂O and CHCl₃. The pH of the aqueous phasewas adjusted to ˜3 with 6N HCl and washed several times with CHCl₃. Thecombined organic fractions were dried (Na₂SO₄), concentrated undervacuum and used directly without further purification (2.84 g, 13.64mmol, 72%): LC-MS (ES) m/z=209 (M+H)⁺.

b)N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (183 mg, 0.88mmol),2-[(2S)-2-amino-3-(3,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(0.3 g, 0.85 mmol) [prepared according to the procedure of Preparation 6except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3,4-difluoro-L-phenylalanine (2.03g, 6.74 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (528 mg, 1.13 mmol) in chloroform (5 mL). DIEA (0.77 mL, 4.41mmol) was added and the mixture stirred overnight at room temperature.The reaction mixture was adsorbed onto silica and purified via columnchromatography (25-75% EtOAc/Hex) affording the title compound (149 mg,30%): LC-MS (ES) m/z=507 (M+H)⁺

c)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(149 mg, 0.265 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1mL). Hydrazine (60 μL, 1.91 mmol) was added and the mixture stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (71 mg, 0.15 mmol, 57% yield): LC-MS (ES) m/z=377 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.96 (d, J=6.06 Hz, 2H) 3.00-3.06 (m, 2H)3.97 (s, 3H) 4.33-4.42 (m, 1H) 6.48 (d, J=1.77 Hz, 1H) 7.14 (s, 1H)7.30-7.42 (m, 2H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.22(s, 3H) 8.35 (d, J=1.26 Hz, 1H) 9.09 (d, J=8.59 Hz, 1H).

Example 147

Preparation ofN-{(1S)-2-amino-1-[(3,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-{(1S)-2-(3,4-dichlorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62mmol) [prepared according to the procedure of Example 146],2-[(2S)-2-amino-3-(3,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(0.26 g, 0.67 mmol) [prepared according to the procedure of Preparation6 except substituting3,4-dichloro-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (2.03g, 6.07 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (376 mg, 0.80 mmol) in chloroform (4 mL). DIEA (0.55 mL, 3.15mmol) was added and the mixture stirred overnight at room temperature.The reaction mixture was adsorbed onto silica and purified via columnchromatography (25-75% EtOAc/Hex) affording the title compound (149 mg,30%): LC-MS (ES) m/z=539 (M+H)⁺

b)N-{(1S)-2-amino-1-[(3,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(3,4-dichlorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(211 mg, 0.34 mmol) in Tetrahydrofuran (THF) (4.5 mL) and Methanol (0.45mL). Hydrazine (75 μL, 2.390 mmol) was added and the mixture stirredovernight at room temperature. Upon completion the mixture was adsorbedonto silica gel and purified via column chromatography (90:10:1CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (83 mg, 0.16 mmol, 48% yield): LC-MS (ES) m/z=411 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.95-3.07 (m, 4H) 3.97 (s, 3H) 4.32-4.43(m, 1H) 6.48 (d, J=1.77 Hz, 1H) 7.29 (dd, J=8.21, 1.89 Hz, 1H) 7.47 (d,J=2.02 Hz, 1H) 7.54 (d, J=8.08 Hz, 1H) 7.60 (d, J=1.77 Hz, 1H) 8.00 (d,J=1.26 Hz, 1H) 8.22 (s, 3H) 8.35 (d, J=1.01 Hz, 1H) 9.11 (d, J=8.59 Hz,1H).

Example 148

Preparation ofN-{(1S)-2-amino-1-[(2,6-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-{(1S)-2-(2,6-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62mmol) [prepared according to the procedure of Example 146],2-[(2S)-2-amino-3-(2,6-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(231 mg, 0.69 mmol) [prepared according to the procedure of Preparation18] and PyBrop (353 mg, 0.75 mmol) in chloroform (8 mL). DIEA (0.64 mL,3.66 mmol) was added and the mixture stirred overnight at roomtemperature. The reaction mixture was adsorbed onto silica and purifiedvia column chromatography (25-75% EtOAc/Hex) affording the titlecompound (149 mg, 0.21 mmol, 30%): LC-MS (ES) m/z=507 (M+H)⁺

b)N-{(1S)-2-amino-1-[(2,6-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(2,6-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(168 mg, 0.32 mmol) in Tetrahydrofuran (THF) (3.6 mL) and Methanol (0.4mL). Hydrazine (70 μL, 2.23 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (101 mg, 0.214 mmol, 68%): LC-MS (ES) m/z=377 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.92-3.03 (m, 3H) 3.17 (m, 1H) 3.97 (s, 3H)4.46 (m, 1H) 6.47 (d, J=1.77 Hz, 1H) 7.05 (t, J=7.83 Hz, 2H) 7.27-7.38(m, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.23 (d, J=1.26Hz, 4H) 8.92 (d, J=8.59 Hz, 1H).

Example 149

Preparation ofN-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (257 mg, 0.93mmol) [prepared according to the procedure of Example 146],2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(476 mg, 0.81 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) inChloroform (15 mL). DIEA (0.808 mL, 4.63 mmol) was added and thereaction stirred overnight at room temperature. The mixture was adsorbedonto silica and purified via column chromatography (25-75% EtOAc/Hex)affording the title compound (225 mg, 34%): LC-MS (ES) m/z=507 (M+H)⁺

b)N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(225 mg, 0.31 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (0.8mL). Hydrazine (60 μL, 1.91 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH). Thecompound was further purified on reverse-phase HPLC (C18 column:H₂O/CH₃CN, 95-5%) affording the TFA salt which was neutralized on silica(90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (90.5 mg, 0.19 mmol, 63%): LC-MS (ES) m/z=377 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.95-3.01 (m, 2H) 3.03-3.10 (m, 2H) 3.92-3.98(m, 3H) 4.41-4.51 (m, 1H) 6.47 (d, J=1.77 Hz, 1H) 7.05-7.13 (m, 1H) 7.20(td, J=9.09, 4.55 Hz, 1H) 7.27 (ddd, J=9.09, 5.81, 3.28 Hz, 1H) 7.47 (d,J=1.77 Hz, 1H) 7.99 (d, J=1.52 Hz, 1H) 8.18 (s, 3H) 8.29 (d, J=1.26 Hz,1H) 9.03 (d, J=8.84 Hz, 1H).

Example 150

Preparation ofN-{(1S)-2-amino-1-[(2,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-{(1S)-2-(2,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (222 mg, 0.80mmol) [prepared according to the procedure of Example 146],2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(331 mg, 0.78 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (1.0 g, 4.97 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (448 mg, 0.96 mmol) inchloroform (10 mL). DIEA (700 μL, 4.01 mmol) was added and the reactionstirred overnight at room temperature. The reaction mixture was adsorbedonto silica and purified via column chromatography (25-75% EtOAc/Hex)affording the title compound (249 mg, 0.36 mmol, 46%): LC-MS (ES)m/z=507 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(2,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(2,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(249 mg, 0.36 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (1 mL).Hydrazine (80 μL, 2.55 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH). Thecompound was further purified on reverse-phase HPLC (C18 column:H₂O/CH₃CN, 95-5%) affording the TFA salt which was neutralized on silica(90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (81 mg, 0.18 mmol, 50%): LC-MS (ES) m/z=377 (M+H)⁺, ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.88-2.98 (m, 2H) 2.98-3.09 (m, 2H) 3.93-3.98 (m,3H) 4.38-4.47 (m, 1H) 6.47 (d, J=1.77 Hz, 1H) 7.00 (td, J=8.46, 2.27 Hz,1H) 7.19 (td, J=9.85, 2.53 Hz, 1H) 7.38-7.45 (m, 1H) 7.47 (d, J=1.77 Hz,1H) 7.99 (d, J=1.26 Hz, 1H) 8.18 (br. s, 3H) 8.27 (d, J=1.26 Hz, 1H)8.99 (d, J=8.59 Hz, 1H).

Example 151

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 125 mL sealed flask was added methyl4-bromo-5-methyl-2-thiophenecarboxylate (1.56 g, 6.64 mmol) [Preparedaccording to the procedure of Preparation 10],1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.67 g, 8.03 mmol) [prepared according to the procedure of Preparation7], K₂CO₃ (2.76 g, 19.97 mmol) and Pd(PtBu₃)₂ (170 mg, 0.33 mmol) in1,4-Dioxane (27 ml) and water (7 ml). The reaction mixture was heated to85° C. in a sealed tube for 3 hours, cooled to room temperature andpartitioned between H₂O and CHCl₃. The organic fraction was dried(Na₂SO₄), adsorbed onto silica and purified via column chromatography(0-15% EtOAc/Hexane). (385 mg, 1.4 mmol, 30%): LC-MS (ES) m/z=237(M+H)⁺.

b) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a 100 mL round-bottomed flask was added methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.34 g,5.67 mmol) in Tetrahydrofuran (THF) (31 ml). 6N NaOH (31 ml, 186 mmol)was added and the reaction mixture stirred at 70° C. overnight. Thereaction mixture was neutralized by slow addition of 6N HCl andpartitioned between CHCl₃ and H₂O. The layers were separated, theorganic layer dried with Na₂SO₄ and solvent removed. The resulting solidwas used without further purification (0.71 g, 2.81 mmol, 96%): LC-MS(ES) m/z=223 (M+H)⁺.

c)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201mg, 0.91 mmol),2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(301 mg, 0.87 mmol) [Prepared according to Preparation 6 exceptsubstitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 14.95 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (519 mg, 1.11 mmol) in chloroform (9 mL). DIEA (790 μL, 4.52mmol) was added and the mixture stirred overnight at room temperature.The reaction mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (247 mg,45%): LC-MS (ES) m/z=553 (M+H)⁺.

d)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(374 mg, 0.64 mmol) in Tetrahydrofuran (THF) (6 mL) and Methanol (600μL). Hydrazine (125 μL, 3.98 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified by column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (135 mg, 0.27 mmol, 42% yield): LC-MS (ES) m/z=423 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.37 (s, 3H) 2.95-3.11 (m, 4H) 3.78 (s, 3H)4.32-4.42 (m, 1H) 6.34 (d, J=1.77 Hz, 1H) 7.48-7.56 (m, 3H) 7.58-7.61(m, 1H) 7.67 (s, 1H) 8.04 (s, 1H) 8.21 (s, 3H) 8.98 (d, J=8.59 Hz, 1H).

Example 152

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201mg, 0.91 mmol) [prepared according to the procedure of Example 95],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(301 mg, 0.87 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (519 mg, 1.11 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (186 mg,32%): LC-MS (ES) m/z=553 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(185 mg, 0.34 mmol) in Tetrahydrofuran (THF) (10 mL) and Methanol (1mL). Hydrazine (63 μL, 2.0 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (101 mg, 0.24 mmol, 72%): LC-MS (ES) m/z=393 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.90-3.1 (m, 4H) 3.85 (s, 3H) 4.33 (s, 1H) 6.48(d, J=1.77 Hz, 1H) 7.10 (t, J=8.84 Hz, 2H) 7.32 (dd, J=8.46, 5.68 Hz,2H) 7.55 (d, J=2.02 Hz, 1H) 8.19 (s, 3H) 8.23-8.28 (m, 1H) 9.25 (d,J=8.59 Hz, 1H).

Example 153

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (226mg, 0.93 mmol) [prepared according to the procedure of Example 95],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(519 mg, 1.349 mmol) [prepared according to Preparation 6 exceptsubstitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (515 mg, 1.1 mmol) in chloroform (10 mL). DIEA (820 μL, 4.70mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (379 mg,69%): LC-MS (ES) m/z=573 (M+H)⁺.

b)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(378 mg, 0.64 mmol) in Tetrahydrofuran (THF) (10 mL) and Methanol (1mL). Hydrazine (122 μL, 3.89 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified by column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (222 mg, 0.41 mmol, 64%): LC-MS (ES) m/z=443 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.05 (d, J=6.82 Hz, 4H) 3.84 (s, 3H) 4.37 (d,J=5.05 Hz, 1H) 6.46 (d, J=1.77 Hz, 1H) 7.49-7.57 (m, 3H) 7.58-7.61 (m,1H) 7.67 (s, 1H) 8.20 (s, 3H) 8.24 (s, 1H) 9.31 (d, J=8.84 Hz, 1H).

Example 154

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200mg, 0.90 mmol) [Prepared according to the procedure of Example 151],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(288 mg, 0.86 mmol) [Prepared according to Preparation 6 exceptsubstitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (162 mg,32%): LC-MS (ES) m/z=503 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(162 mg, 0.29 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (300μL). Hydrazine (58 μL, 1.85 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH). Thecompound was further purified on reverse-phase HPLC (C18 column:H₂O/CH₃CN, 95-5%) affording the TFA salt which was neutralized on silica(90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (222 mg, 0.41 mmol, 64%): LC-MS (ES) m/z=373 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.38 (s, 3H) 2.89-3.02 (m, 4H) 3.79 (s, 3H)4.26-4.48 (m, 1H) 6.36 (d, J=1.77 Hz, 1H) 7.10 (t, J=8.72 Hz, 2H)7.26-7.35 (m, 2H) 7.52 (d, J=1.77 Hz, 1H) 8.02 (s, 1H) 8.17 (s, 3H) 8.88(d, J=8.59 Hz, 1H).

Example 155

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200mg, 0.90 mmol) [Prepared according to the procedure of Example 151],2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(291 mg, 0.87 mmol) [Prepared according to the procedure of preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g,17.8 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52mmol) was added and the mixture stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (250 mg,50%): LC-MS (ES) m/z=503 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(250 mg, 0.45 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (400μL). Hydrazine (66 μL, 2.10 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH). Thecompound was further purified on reverse-phase HPLC (C18 column:H₂O/CH₃CN, 95-5%) affording the TFA salt which was neutralized on silica(90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (142 mg, 0.31 mmol, 70%): LC-MS (ES) m/z=373 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.38 (s, 3H) 2.92-3.04 (m, 4H) 3.79 (s, 3H)4.30-4.43 (m, 1H) 6.36 (d, J=1.77 Hz, 1H) 7.02 (td, J=8.53, 2.15 Hz, 1H)7.13 (t, J=7.83 Hz, 2H) 7.26-7.35 (m, 1H) 7.52 (d, J=2.02 Hz, 1H) 8.04(s, 1H) 8.19 (s, 3H) 8.93 (d, J=8.34 Hz, 1H).

Example 156

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

NBS (747 mg, 4.20 mmol) was added in portions to a 50 mL sealed tubereactor containing methyl4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (860 mg, 3.48 mmol)[prepared according to the procedure of Example 37] in Tetrahydrofuran(THF) (17 mL) at room temperature. The mixture was heated to 70° C. for1.5 hours, cooled to room temperature and partitioned between CHCl₃ andH₂O. The organic layer was dried with Na₂SO₄, adsorbed onto silica andpurified via column chromatography (20-40% EtOAc/hexanes) affording thetitle compound (867 mg, 83%): LC-MS (ES) m/z=303 (M+H)⁺.

b) methyl4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 20 mL sealed tube reactor was added methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (505 mg,1.68 mmol), cyclopropylboronic acid (447 mg, 5.20 mmol), CesiumCarbonate (1.90 g, 5.84 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (43.6 mg,0.05 mmol) in Tetrahydrofuran (THF) (8.5 mL). The reaction was heated to70° C. for 1.5 hours, cooled and partitioned between CHCl₃ and H₂O. Theorganic layer was dried with Na₂SO₄, adsorbed onto silica and purifiedvia column chromatography (20-40% EtOAc/Hexane) affording the titlecompound (0.42 g, 1.60 mmol, 95%): LC-MS (ES) m/z=251 (M+H)⁺.

c) 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a 100 mL round-bottomed flask was added methyl4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.42g, 1.60 mmol) in Tetrahydrofuran (THF) (8 ml). 6N NaOH (8 ml, 48.0 mmol)was added slowly and the reaction stirred at 70° C. overnight. Thereaction was cooled and partitioned between CHCl₃ and H₂O. The pH of theaqueous layer was adjusted to ˜3 by the addition of 6N HCl. The layerswere separated, the organic layer dried with Na₂SO₄ and solvent removedaffording the title compound (0.42 g, 1.60 mmol, 95%) which was usedwithout further purification: LC-MS (ES) m/z=249 (M+H)⁺.

d)4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(105 mg, 0.42 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(152 mg, 0.39 mmol) [prepared according to Preparation 6] and PyBrop(246 mg, 0.52 mmol) in Chloroform (6 mL). DIEA (370 μL, 2.19 mmol) wasadded and the mixture stirred overnight at room temperature. The mixturewas adsorbed onto silica and purified via column chromatography (25-70%EtOAc/Hex) affording the title compound (171 mg, 66%): LC-MS (ES)m/z=579 (M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(102 mg, 0.18 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (2 mL).Hydrazine (40 μL, 1.27 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (65 mg, 0.12 mmol, 66% yield): LC-MS (ES) m/z=449 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.45-0.54 (m, 2H) 0.76-0.83 (m, 2H)1.62-1.71 (m, 1H) 3.03-3.21 (m, 4H) 3.82 (s, 3H) 4.46-4.56 (m, 1H) 7.21(s, 1H) 7.42 (t, J=7.45 Hz, 1H) 7.53 (t, J=7.45 Hz, 1H) 7.66 (dd,J=19.96, 7.58 Hz, 2H) 7.95 (d, J=1.26 Hz, 1H) 8.18 (s, 3H) 8.24 (d,J=1.26 Hz, 1H) 9.11 (d, J=9.09 Hz, 1H).

Example 157

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 5 mL sealed tube reactor was added methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (473 mg,1.57 mmol) [prepared according to the procedure of Example 156],pyridine-triethenylboroxine (1:1) (666 mg, 2.77 mmol), Pd(PtBu₃)₂ (16.8mg, 0.03 mmol) and Cs₂CO₃ (1.72 g, 5.28 mmol) in 1,4-Dioxane (6.3 mL)and water (1.6 mL). The reaction was heated at 70° C. for 2 hours andpartitioned between CHCl₃ (75 mL)/H₂O (75 mL). The organic layer wasdried with Na₂SO₄, adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hexane) affording the desired product:LC-MS (ES) m/z=249 (M+H)⁺.

b) methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 100 mL round-bottomed flask was added methyl4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate and 10%Pd/C in ethyl acetate (15 mL). The mixture was evacuated slightly,refilled with H₂ from a balloon and stirred vigorously under anatmosphere of H₂ for 1 hour. The reaction was filtered through a 0.2 μmPTFE membrane filter and used without further purification (153 mg, 0.60mmol, 87%): LC-MS (ES) m/z=251 (M+H)⁺.

c) 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a 100 mL round-bottomed flask was added methyl4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (192 mg,0.77 mmol) in Tetrahydrofuran (THF) (4 mL). 6N NaOH (4 mL, 24.0 mmol)was added slowly, the reaction stirred at 70° C. overnight. The reactionwas cooled to room temperature, partitioned between CHCl₃ and H₂O andthe pH of the aqueous layer adjusted to pH 3 by the addition of 6N HCl.The layers were separated, the organic layer dried with Na₂SO₄ andsolvent removed affording the title compound (181 mg, quant.) usedwithout further purification: LC-MS (ES) m/z=237 (M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (106 mg,0.45 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(164 mg, 0.43 mmol) [prepared according to Preparation 6] and PyBrop(254 mg, 0.54 mmol) in Chloroform (6 mL). DIEA (400 μL, 2.29 mmol) wasadded and the reaction stirred overnight at room temperature. Themixture was adsorbed onto silica and purified via column chromatography(25-70% EtOAc/Hex) affording the title compound (182 mg, 0.32 mmol,71%): LC-MS (ES) m/z=567 (M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(101 mg, 0.18 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (2 mL).Hydrazine (40 μL, 1.27 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (65 mg, 0.12 mmol, 68%): LC-MS (ES) m/z=437 (M+H)⁺, ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.10 (t, J=7.45 Hz, 3H) 2.44 (q, J=7.41 Hz, 2H)2.94-3.17 (m, 4H) 3.80 (s, 3H) 4.41-4.57 (m, 1H) 7.37-7.45 (m, 2H) 7.53(t, J=7.45 Hz, 1H) 7.66 (dd, J=19.96, 7.58 Hz, 2H) 7.88 (d, J=1.01 Hz,1H) 8.16 (s, 4H) 9.10 (d, J=8.84 Hz, 1H).

Example 158

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicAcid

NCS (1.355 g, 10.15 mmol) was added in portions to a 150 mL sealed tubereactor containing methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.0 g,8.46 mmol) [prepared according to the procedure of Preparation 10] inTetrahydrofuran (THF) (40 ml) at room temperature. The mixture washeated to 70° C. for 2 h. 6N NaOH (28 ml, 168 mmol) was added and themixture stirred at 70° C. for an additional 2 h. The mixture was cooledto room temperature and partitioned between CHCl₃ and H₂O. The pH of theaqueous layer was adjusted to ˜3 by the addition of 6N HCl. The aqueousphase was washed several times with DCM and the combined organicfractions were dried with Na₂SO₄ and concentrated affording the titlecompound (2.36 g, 9.19 mmol, quant.): LC-MS (ES) m/z=257 (M+H)⁺.

b)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicacid (181 mg, 0.70 mmol),2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(250 mg, 0.65 mmol) [Prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (399 mg, 0.85 mmol) in chloroform (8 mL). DIEA (620 μL, 3.55mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (319 mg,0.50 mmol, 71%): LC-MS (ES) m/z=587 (M+H)⁺.

c)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide(319 mg, 0.50 mmol) in Tetrahydrofuran (THF) (4.9 mL) and Methanol (0.5mL). Hydrazine (119 μL, 3.79 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified by column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (204 mg, 0.39 mmol, 79%): LC-MS (ES) m/z=457 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.33 (s, 3H) 2.95-3.10 (m, 4H) 3.71 (s, 3H)4.31-4.41 (m, 1H) 7.49-7.61 (m, 3H) 7.66 (s, 1H) 7.69 (s, 1H) 7.94 (s,1H) 8.16 (s, 3H) 8.90 (s, 1H).

Example 159

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicAcid

NBS (1.84 g, 10.33 mmol) was added in portions to a 150 mL sealed tubereactor containing methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2 g, 8.46mmol) [prepared according to the procedure of Preparation 10] inTetrahydrofuran (THF) (40 ml) at room temperature. The mixture washeated to 70° C. for 1 h. 6N NaOH (28 ml, 168 mmol) was then added andthe mixture stirred at 70° C. for 2 h. The mixture was partitionedbetween CHCl₃ and H₂O and the aqueous layer was made acidic with 6N HCl.The aqueous phase was washed several times with CHCl₃ and the organicfractions were combined, dried over Na₂SO₄ and concentrated affordingthe title compound (2.68 g, 8.9 mmol, quant.): LC-MS (ES) m/z=302(M+H)⁺.

b)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(256 mg, 0.85 mmol),2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(1272 mg, 3.80 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (485 mg, 1.03 mmol) in Chloroform (8.5 mL). DIEA (750 μL,4.29 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=583 (M+H)⁺.

c)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(133 mg, 0.21 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL).Hydrazine (50 μL, 1.59 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (90 mg, 0.17 mmole, 83%): LC-MS (ES) m/z=453 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.33 (s, 3H) 2.82-3.08 (m, 4H) 3.72 (s, 3H)4.24-4.39 (m, 1H) 7.11 (t, J=8.84 Hz, 2H) 7.26-7.35 (m, 2H) 7.69 (s, 1H)7.89 (s, 1H) 8.03-8.25 (m, 3H) 8.73-8.90 (m, 1H).

Example 160

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicacid (276 mg, 1.08 mmol) [Prepared according to the procedure of Example158],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(317 mg, 0.95 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (612 mg, 1.31 mmol) in Chloroform (14 mL). DIEA (940 μL, 5.38mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (319 mg,0.50 mmol, 71%): LC-MS (ES) m/z=537 (M+H)⁺.

c)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(145 mg, 0.25 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (60 μL, 1.91 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified by column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (88 mg, 0.19 mmol, 77%): LC-MS (ES) m/z=407 (M+H)⁺, ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.34 (s, 3H) 2.81-3.10 (m, 4H) 3.72 (s, 3H)4.25-4.40 (m, 1H) 7.10 (t, J=8.84 Hz, 2H) 7.31 (dd, J=8.21, 5.68 Hz, 2H)7.69 (s, 1H) 7.94 (s, 1H) 8.15 (s, 3H) 8.85 (s, 1H).

Example 161

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicacid (187 mg, 0.73 mmol) [prepared according to the procedure of Example158],2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(233 mg, 0.70 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g,17.8 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (412 mg, 0.88 mmol) in Chloroform (9 mL). DIEA (640 μL, 3.66mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (180 mg,0.30 mmol, 42%): LC-MS (ES) m/z=537 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(186 mg, 0.31 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (76 μL, 2.42 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (108 mg, 0.231, 74%): LC-MS (ES) m/z=407 (M+H)⁺, ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.34 (s, 3H) 2.91-3.03 (m, 4H) 3.71 (s, 3H)4.31-4.41 (m, 1H) 7.02 (td, J=8.59, 2.02 Hz, 1H) 7.13 (t, J=7.07 Hz, 2H)7.26-7.36 (m, 1H) 7.69 (s, 1H) 7.95 (s, 1H) 8.15 (s, 3H) 8.88 (d, J=6.32Hz, 1H).

Example 162

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(191 mg, 0.63 mmol) [prepared according to the procedure of Example159],2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(209 mg, 0.62 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g,17.8 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (359 mg, 0.77 mmol) in chloroform (7 mL). DIEA (560 μL, 3.21mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (171 mg,0.29 mmol, 46%): LC-MS (ES) m/z=583 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(171 mg, 0.29 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL).Hydrazine (66 μL, 2.10 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified by column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (123 mg, 0.26 mmol, 88%): LC-MS (ES) m/z=453 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.33 (s, 3H) 2.91-3.03 (m, 4H) 3.72 (s, 3H)4.31-4.41 (m, 1H) 7.02 (td, J=8.46, 2.02 Hz, 1H) 7.12 (d, J=7.33 Hz, 2H)7.27-7.35 (m, 1H) 7.64-7.71 (m, 1H) 7.92 (s, 1H) 8.14 (s, 3H) 8.79-8.93(m, 1H).

Example 163

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(180 mg, 0.60 mmol) [prepared according to the procedure of Example159],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(203 mg, 0.58 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (340 mg, 0.72 mmol) in Chloroform (6 mL). DIEA (530 μL, 3.03mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (259 mg,0.41 mmol, 69%): LC-MS (ES) m/z=633 (M+H)⁺.

b)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide(259 mg, 0.41 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL).Hydrazine (90 μL, 2.87 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (172 mg, 0.33 mmol, 80%): LC-MS (ES) m/z=503 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H) 3.03 (d, J=6.06 Hz, 4H) 3.71 (d,J=5.81 Hz, 3H) 4.31-4.41 (m, 1H) 7.49-7.56 (m, 2H) 7.60 (d, J=6.82 Hz,1H) 7.64-7.71 (m, 2H) 7.93 (d, J=12.88 Hz, 1H) 8.18 (s, 3H) 8.88-8.99(m, 1H).

Example 164

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea) methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

NBS (2.03 g, 11.41 mmol) was added in portions to a 75 mL sealed tubereactor containing methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.1 g,8.89 mmol) [prepared according to the procedure of Preparation 10] inTetrahydrofuran (THF) (40 ml) at room temperature. The mixture washeated to 70° C. for 1 hour. The reaction mixture was partitionedbetween CHCl₃ and H₂O, the organic layer dried with Na₂SO₄, the reactionmixture adsorbed onto silica and purified via column chromatography(15-40% EtOAc/Hex) affording the title compound (2.57 g, 8.15 mmol,92%): LC-MS (ES) m/z=316 (M+H)⁺.

b) methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

To a 350 mL sealed flask reactor was added methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate(2.57 g, 8.15 mmol), trimethylboroxine (2.27 ml, 16.31 mmol), K₂CO₃(3.47 g, 25.1 mmol) and Pd(dppf)Cl₂ (426 mg, 0.83 mmol) inN,N-Dimethylformamide (DMF) (41 ml). The reaction was heated at 110° C.for 1 hour. The mixture was partitioned between CHCl₃/H₂O, organic layerseparated and dried with Na₂SO₄. The resulting material was adsorbedonto silica and purified via column chromatography (0-15% EtOAc/Hexane)affording the title compound (1.3 g, 4.76 mmol, 58%): LC-MS (ES) m/z=251(M+H)⁺.

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic Acid

To a 100 mL round-bottomed flask was added methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (1.31g, 5.23 mmol) in Tetrahydrofuran (THF) (25 mL). 6N NaOH (30 mL, 180mmol) was added slowly and the reaction stirred at 70° C. overnight. Thereaction was cooled to room temperature, partitioned between CHCl₃ andH₂O and the pH of the aqueous layer adjusted to pH 3 by the addition of6N HCl. The layers were separated, the organic layer was dried withNa₂SO₄ and the solvent was removed affording the title compound (1.3 g,5.5 mmol, quant.) which was used without further purification: LC-MS(ES) m/z=237 (M+H)⁺.

d)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(170 mg, 0.68 mmol),2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(256 mg, 0.67 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (387 mg, 0.83 mmol) in chloroform (7 mL). DIEA (600 μL, 3.44mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (311 mg,0.55 mmol, 80%): LC-MS (ES) m/z=567 (M+H)⁺.

e)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide(311 mg, 0.55 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1.4mL). Hydrazine (122 μL, 3.89 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (234 mg, 0.44 mmol, 79%): LC-MS (ES) m/z=437 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.87 (s, 3H) 2.26 (s, 3H) 3.03 (d, J=6.82 Hz,4H) 3.62 (s, 3H) 4.31-4.41 (m, 1H) 7.38 (s, 1H) 7.49-7.56 (m, 2H)7.58-7.61 (m, 1H) 7.65 (s, 1H) 7.87 (s, 1H) 8.20 (s, 3H) 8.89 (d, J=8.59Hz, 1H).

Example 165

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(207 mg, 0.83 mmol) [prepared according to the procedure of Example164],2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(279 mg, 0.83 mmol) [Prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g,17.8 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (469 mg, 1.00 mmol) in chloroform (8 mL). DIEA (730 μL, 4.18mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (209 mg,0.36 mmol, 43%): LC-MS (ES) m/z=517 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(201 mg, 0.39 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (86 μL, 2.74 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (163 mg, 0.34 mmol, 87%): LC-MS (ES) m/z=387 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.88 (s, 3H) 2.27 (s, 3H) 2.87-3.09 (m, 4H)3.17 3.63 (s, 3H) 4.28-4.45 (m, 1H) 6.97-7.06 (m, 1H) 7.13 (t, J=7.20Hz, 2H) 7.27-7.35 (m, 1H) 7.38 (s, 1H) 7.89 (s, 1H) 8.20 (s, 3H) 8.88(d, J=7.58 Hz, 1H).

Example 166

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(253 mg, 1.02 mmol) [prepared according to the procedure of Example164],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(335 mg, 1.00 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (574 mg, 1.23 mmol) in chloroform (10 mL). DIEA (930 μL, 5.32mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (132 mg,0.25 mmol, 24%): LC-MS (ES) m/z=517 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(132 mg, 0.26 mmol) in Tetrahydrofuran (THF) (2 mL) and Methanol (1 mL).Hydrazine (57 μL, 1.82 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (95:5:0.5 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (104 mg, 0.22 mmol, 84%): LC-MS (ES) m/z=387 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.88 (s, 3H) 2.27 (s, 3H) 2.84-3.11 (m, 4H)3.63 (s, 3H) 4.24-4.39 (m, 1H) 7.10 (t, J=8.72 Hz, 2H) 7.31 (dd, J=8.21,5.68 Hz, 2H) 7.38 (s, 1H) 7.87 (s, 1H) 8.18 (s, 3H) 8.83 (s, 1H).

Example 167

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylicAcid

NBS (1.243 g, 6.98 mmol) was added in portions to a 150 mL sealed tubereactor containing methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.47 g,5.73 mmol) [Prepared according to the procedure of Example 151] inTetrahydrofuran (THF) (40 ml) at room temperature. The mixture washeated to 70° C. for 1 h. 6N NaOH (20 ml, 120 mmol) was then added andthe mixture stirred at 70° C. for an additional 2 h. The mixture waspartitioned between CHCl₃ and H₂O, the organic layer dried with Na₂SO₄and concentrated affording the title compound which was used withoutfurther purification (385 mg, 1.4 mmol, 30%): LC-MS (ES) m/z=302 (M+H)⁺.

b)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid(204 mg, 0.60 mmol),2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(215 mg, 0.64 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g,17.7 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (380 mg, 0.81 mmol) in chloroform (6 mL). DIEA (570 μL, 3.26mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (247 mg,45%): LC-MS (ES) m/z=603 (M+H)⁺.

c)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(133 mg, 0.22 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1.2mL). Hydrazine (50 μL, 1.59 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (145 mg, 0.30 mmol, 66% yield): LC-MS (ES) m/z=473 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.91-3.03 (m, 4H) 3.77 (s, 3H) 4.30-4.41(m, 1H) 7.04 (td, J=8.53, 2.15 Hz, 1H) 7.12 (d, J=7.07 Hz, 2H) 7.28-7.36(m, 1H) 7.74 (s, 1H) 8.02-8.14 (m, 4H) 9.06 (s, 1H).

Example 168

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (264 mg, 0.95 mmol) [prepared according to the procedure of Example96],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(306 mg, 0.80 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (450 mg, 0.96 mmol) in chloroform (7 mL). DIEA (660 μl, 3.78mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (303 mg,0.44 mmol, 56%): LC-MS (ES) m/z=607 (M+H)⁺.

b)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(303 mg, 0.50 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1.5mL). Hydrazine (120 μL, 3.82 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (177 mg, 0.31 mmol, 61% yield): LC-MS (ES) m/z=479 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.97-3.08 (m, 4H) 3.76 (s, 3H) 4.28-4.44(m, 1H) 7.50-7.61 (m, 3H) 7.66 (s, 1H) 7.71-7.75 (m, 1H) 8.10 (s, 4H)9.16 (d, J=8.59 Hz, 1H).

Example 169

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamidea)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid(183 mg, 0.54 mmol) [prepared according to the procedure of Example167],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(201 mg, 0.52 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (298 mg, 0.64 mmol) in chloroform (5 mL). DIEA (470 μL, 2.69mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (246 mg,0.36 mmol, 69%): LC-MS (ES) m/z=653 (M+H)⁺.

d)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(246 mg, 0.38 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (0.083 mL, 2.64 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (134 mg, 0.22 mmol, 57% yield): LC-MS (ES) m/z=523 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.04 (d, J=4.55 Hz, 4H) 3.76 (s, 3H)4.29-443 (m, 1H) 7.50-7.61 (m, 3H) 7.66 (s, 1H) 7.70-7.75 (m, 1H)8.06-8.18 (m, 4H) 9.17 (s, 1H).

Example 170

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamidea)4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid(340 mg, 1.00 mmol) [prepared according to the procedure of Example167],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(374 mg, 1.12 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (626 mg, 1.34 mmol) in chloroform (10 mL). DIEA (980 μL, 5.61mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (229 mg,0.35 mmol, 31%): LC-MS (ES) m/z=603 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(229 mg, 0.38 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1.2mL). Hydrazine (90 μL, 2.87 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (99 mg, 0.17 mmol, 45% yield): LC-MS (ES) m/z=473 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.90 (d, J=6.82 Hz, 2H) 2.95-3.06 (m, 2H)3.77 (s, 3H) 4.27-4.39 (m, 1H) 7.11 (t, J=8.72 Hz, 2H) 7.26-7.35 (m, 2H)7.74 (s, 1H) 8.01-8.21 (m, 4H) 9.06 (s, 1H).

Example 171

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (320 mg, 1.16 mmol) [prepared according to the procedure of Example168],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(318 mg, 0.95 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (535 mg, 1.14 mmol) in Chloroform (9.5 mL). DIEA (840 μl,4.81 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(106 mg, 0.16 mmol, 17%): LC-MS (ES) m/z=557 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(106 mg, 0.19 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1.5mL). Hydrazine (45 μL, 1.43 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (65 mg, 0.12 mmol, 65% yield): LC-MS (ES) m/z=429 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.82-3.10 (m, 4H) 3.77 (s, 3H) 4.27-4.38(m, 1H) 7.11 (t, J=8.72 Hz, 2H) 7.26-7.35 (m, 2H) 7.68-7.76 (m, 1H) 8.10(s, 4H) 9.11 (d, J=7.33 Hz, 1H).

Example 172

Preparation ofN-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylicacid (219 mg, 0.85 mmol) [prepared according to the procedure of Example158],2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(290 mg, 0.82 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (481 mg, 1.03 mmol) inchloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reactionstirred overnight at room temperature. The mixture was adsorbed ontosilica and purified via column chromatography (25-70% EtOAc/Hex)affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES)m/z=555 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide(246 mg, 0.44 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (100 μL, 3.19 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (147 mg, 0.28 mmol, 64% yield): LC-MS (ES) m/z=425 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3H) 2.93-3.07 (m, 4H) 3.71 (s, 3H)4.34-4.50 (m, 1H) 7.04-7.14 (m, 1H) 7.19 (td, J=9.03, 4.67 Hz, 2H) 7.69(s, 1H) 7.93 (s, 1H) 8.14 (s, 3H) 8.87 (d, J=8.59 Hz, 1H).

Example 173

Preparation ofN-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (171mg, 0.77 mmol) [prepared according to the procedure of Example 151],2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(270 mg, 0.77 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (436 mg, 0.93 mmol) inchloroform (7.5 mL). DIEA (680 μL, 3.89 mmol) was added and the reactionstirred overnight at room temperature. The mixture was adsorbed ontosilica and purified via column chromatography (25-70% EtOAc/Hex)affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES)m/z=521 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(243 mg, 0.47 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (0.103 mL, 3.27 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (132 mg, 0.27 mmol, 58% yield): LC-MS (ES) m/z=391 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.38 (s, 3H) 2.87-3.10 (m, 4H) 3.78 (s, 3H)4.36-4.47 (m, 1H) 6.35 (d, J=1.77 Hz, 1H) 7.05-7.13 (m, 1H) 7.16-7.28(m, 2H) 7.52 (d, J=1.52 Hz, 1H) 8.00 (s, 1H) 8.16 (s, 3H) 8.88 (d,J=8.59 Hz, 1H).

Example 174

Preparation ofN-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid(208 mg, 0.88 mmol) [prepared according to the procedure of Example164],2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(288 mg, 0.82 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (503 mg, 1.07 mmol) inChloroform (8.5 mL). DIEA (770 μL, 4.41 mmol) was added and the reactionstirred overnight at room temperature. The mixture was adsorbed ontosilica and purified via column chromatography (25-70% EtOAc/Hex)affording the title compound (292 mg, 0.55 mmol, 62%): LC-MS (ES)m/z=535 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide(292 mg, 0.55 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (1 mL)Hydrazine (120 μL, 3.82 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (163 mg, 0.32 mmol, 59% yield): LC-MS (ES) m/z=405 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.88 (s, 3H) 2.27 (s, 3H) 2.94-3.06 (m, 4H)3.63 (s, 3H) 4.35-4.49 (m, 1H) 7.05-7.12 (m, 1H) 7.16-7.27 (m, 2H) 7.38(s, 1H) 7.86 (s, 1H) 8.16 (s, 3H) 8.83 (d, J=8.84 Hz, 1H).

Example 175

Preparation ofN-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (235 mg, 0.85 mmol) [prepared according to the procedure of Example96],2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(290 mg, 0.82 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (479 mg, 1.02 mmol) inchloroform (8.5 mL). DIEA (742 μL, 4.25 mmol) was added and the reactionstirred overnight at room temperature. The mixture was adsorbed ontosilica and purified via column chromatography (25-70% EtOAc/Hex)affording the title compound (174 mg, 0.30 mmol, 36%): LC-MS (ES)m/z=575 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide(174 mg, 0.30 mmol) in Tetrahydrofuran (THF) (3.6 mL) and Methanol (1mL). Hydrazine (70 μL, 2.23 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (115 mg, 0.21 mmol, 70% yield): LC-MS (ES) m/z=445 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.88-3.09 (m, 4H) 3.76 (s, 3H) 4.33-4.48(m, 1H) 7.06-7.15 (m, 1H) 7.20 (td, J=9.09, 4.55 Hz, 2H) 7.74 (s, 1H)8.10 (s, 1H) 8.13 (s, 3H) 9.14 (d, J=8.84 Hz, 1H).

Example 176

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 350 mL sealed flask reactor was added methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (3.45 g,11.46 mmol) [prepared according to the procedure of Example 156],trimethylboroxine (2.7 ml, 19.40 mmol), K₂CO₃ (4.75 g, 34.4 mmol) andPd(dppf)Cl₂ (599 mg, 1.17 mmol) in N,N-Dimethylformamide (DMF) (57 mL).The reaction was heated at 110° C. for 1 hour, cooled to roomtemperature and partitioned between CHCl₃/H₂O. The organic layer wasseparated, dried with Na₂SO₄, adsorbed onto silica and purified viacolumn chromatography (0-30% EtOAc/Hexane) affording the title compound(2.07 g, 8.76 mmol, 76%): LC-MS (ES) m/z=251 (M+H)⁺.

b) methyl4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

NCS (1.78 g, 13.09 mmol) was added in portions to a 125 mL sealed tubereactor containing methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.07 g, 8.76mmol) in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixturewas heated to 100° C. for 1 hour. Upon completion the product waspartitioned between CHCl₃ and H₂O, the organic layer dried with Na₂SO₄,solvents removed by vacuum distillation affording the title compound(2.18 g, 7.97 mmol, 91%) which was used without further purification:LC-MS (ES) m/z=271 (M+H)⁺.

c) 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a 100 mL round-bottomed flask was added methyl4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.15g, 7.94 mmol) in Tetrahydrofuran (THF) (30 ml). 6N NaOH (30 mL, 180mmol) was added slowly and the reaction stirred at 70° C. overnight. Thereaction was cooled to room temperature, partitioned between CHCl₃ andH₂O and the pH of the aqueous layer adjusted to ˜3 by the addition of 6NHCl. The layers were separated, the organic layer dried with Na₂SO₄ andsolvent removed affording the title compound (1.35 g, 5.26 mmol, 66%)which was used in the next step without further purification LC-MS (ES)m/z=257 (M+H)⁺.

d)4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(294 mg, 1.14 mmol),2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(409 mg, 1.22 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (645 mg, 1.38 mmol) in chloroform (10 mL). DIEA (1 mL, 5.73mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (534 mg,0.92 mmol, 81%): LC-MS (ES) m/z=537 (M+H)⁺.

c)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(534 mg, 0.994 mmol) in Tetrahydrofuran (THF) (9 mL) and Methanol (1mL). Hydrazine (220 μL, 7.01 mmol) was added and the reaction stirredovernight at room temperature. The reaction mixture was adsorbed ontosilica gel and purified via column chromatography (90:10:1CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (354 mg, 0.70 mmol, 70% yield): LC-MS (ES) m/z=407 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.99 (s, 3H) 2.91-3.02 (m, 4H) 3.79 (s, 3H)4.30-4.41 (m, 1H) 7.10 (t, J=8.84 Hz, 2H) 7.27-7.36 (m, 2H) 8.01 (d,J=1.26 Hz, 1H) 8.15 (s, 3H) 8.21 (d, J=1.26 Hz, 1H) 9.04 (d, J=8.34 Hz,1H).

Example 177

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(291 mg, 1.13 mmol) [prepared according to the procedure of Example176],2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(409 mg, 1.22 mmol) [prepared according to the procedure of Preparation6 except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g,17.8 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (654 mg, 1.39 mmol) in chloroform (10 mL). DIEA (1 mL, 5.73mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (427 mg,0.76 mmol, 67%): LC-MS (ES) m/z=537 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(427 mg, 0.79 mmol) in Tetrahydrofuran (THF) (7.5 mL) and Methanol (1mL). Hydrazine (175 μL, 5.58 mmol) was added and the solution stirred at25° C. overnight. The mixture was adsorbed onto silica gel and purifiedvia column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (296 mg, 0.59 mmol, 74% yield): LC-MS (ES) m/z=407 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.99 (s, 3H) 2.95-3.06 (m, 4H) 3.79 (s, 3H)4.33-4.45 (m, 1H) 7.02 (td, J=8.59, 2.02 Hz, 1H) 7.09-7.18 (m, 2H)7.26-7.36 (m, 1H) 8.01 (d, J=1.01 Hz, 1H) 8.16 (s, 3H) 8.22 (s, 1H) 9.07(d, J=8.34 Hz, 1H).

Example 178

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(150 mg, 0.58 mmol) [prepared according to the procedure of Example176], 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione(176 mg, 0.54 mmol) [prepared according to the procedure of Preparation6, except substituting3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (336 mg, 0.72 mmol) in chloroform (6 mL). DIEA (520 μL, 2.98mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (336 mg,0.61 mmol, quant.): LC-MS (ES) m/z=526 (M+H)⁺.

b)N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide(366 mg, 0.697 mmol) in Tetrahydrofuran (THF) (6.5 mL) and Methanol (1mL). Hydrazine (155 μL, 4.94 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (173 mg, 0.35 mmol, 50% yield): LC-MS (ES) m/z=395 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.92 (m, 1H) 0.92-1.01 (m, 1H) 1.13(d, J=6.57 Hz, 2H) 1.22 (d, J=12.88 Hz, 1H) 1.29 (s, 1H) 1.32-1.43 (m,1H) 1.48-1.56 (m, 1H) 1.58 (d, J=5.05 Hz, 1H) 1.63 (s, 3H) 1.73-1.84 (m,1H) 1.99 (s, 3H) 2.94 (d, J=5.31 Hz, 2H) 3.78 (s, 3H) 4.22-4.36 (m, 1H)8.03 (s, 1H) 8.05 (s, 3H) 8.19 (s, 1H) 8.80 (d, J=8.59 Hz, 1H).

Example 179

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(238 mg, 0.93 mmol) [prepared according to the procedure of Example176],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(355 mg, 0.92 mmol) [prepared according to the procedure of Preparation6, except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(5.0 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (532 mg, 1.13 mmol) in chloroform (9.5 mL). DIEA (820 μL,4.70 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(448 mg, 0.72 mmol, 78%): LC-MS (ES) m/z=587 (M+H)⁺.

b)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(468 mg, 0.80 mmol) in Tetrahydrofuran (THF) (7.5 mL) and Methanol (1mL). Hydrazine (175 μL, 5.58 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (321 mg, 0.58 mmol, 72% yield): LC-MS (ES) m/z=457 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.98 (s, 3H) 3.05 (d, J=7.07 Hz, 4H) 3.77(s, 3H) 4.33-4.44 (m, 1H) 7.49-7.57 (m, 2H) 7.58-7.62 (m, 1H) 7.66 (s,1H) 8.01 (d, J=1.26 Hz, 1H) 8.11 (s, 3H) 8.17 (d, J=1.26 Hz, 1H) 9.02(d, J=8.59 Hz, 1H).

Example 180

Preparation ofN-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)5-chloro-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (147mg, 0.61 mmol),2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(216 mg, 0.61 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (341.4 mg, 0.73 mmol) inchloroform (6 mL). DIEA (530 μL, 3.03 mmol) was added and the reactionstirred overnight at room temperature. The mixture was adsorbed ontosilica and purified via column chromatography (25-70% EtOAc/Hex)affording the title compound (233 mg, 0.43 mmol, 71%): LC-MS (ES)m/z=541 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(233 mg, 0.43 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (1 mL).Hydrazine (95 μL, 3.03 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (165 mg, 0.32 mmol, 75% yield): LC-MS (ES) m/z=411 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.88-3.14 (m, 4H) 3.85 (s, 3H) 4.37-4.50(m, 1H) 6.48 (d, J=1.77 Hz, 1H) 7.09 (t, J=8.34 Hz, 1H) 7.19 (dt,J=9.09, 4.55 Hz, 1H) 7.29 (ddd, J=8.84, 5.68, 3.16 Hz, 1H) 7.55 (d,J=1.52 Hz, 1H) 8.22 (s, 3H) 8.27 (s, 1H) 9.32 (d, J=8.84 Hz, 1H).

Example 181

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example109, except substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(184 mg, 0.55 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione[prepared according to Preparation 6]: LC-MS (ES) m/z=401 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.04 (t, J=7.33 Hz, 3H) 2.13-2.33 (m, 5H)2.86-3.08 (m, 4H) 3.60 (s, 3H) 4.27-4.43 (m, 1H) 6.96-7.07 (m, 1H) 7.11(d, J=6.32 Hz, 2H) 7.30 (s, 1H) 7.43 (s, 1H) 7.85 (s, 1H) 8.19 (s, 3H)8.85 (s, 1H).

Example 182

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example109, except substituting 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(207 mg, 0.62 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione[prepared according to Preparation 6]: LC-MS (ES) m/z=401 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.04 (t, J=7.20 Hz, 3H) 2.25 (s, 5H) 2.88-3.00(m, 4H) 3.61 (s, 3H) 4.25-4.40 (m, 1H) 7.01-7.17 (m, 2H) 7.26-7.35 (m,2H) 7.42 (s, 1H) 7.82 (s, 1H) 8.17 (s, 3H) 8.81 (s, 1H).

Example 183

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example109, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(158 mg, 0.41 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione[prepared according to Preparation 6]: LC-MS (ES) m/z=451 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.04 (t, J=7.33 Hz, 3H) 2.24 (s, 5H) 3.03 (d,J=6.32 Hz, 4H) 3.59 (s, 3H) 4.35 (s, 1H) 7.42 (s, 1H) 7.46-7.57 (m, 2H)7.59 (d, J=6.57 Hz, 1H) 7.64 (s, 1H) 7.84 (s, 1H) 8.20 (s, 3H) 8.88 (s,1H).

Example 184

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea) methyl 5-methyl-2-furancarboxylate

To a 200 mL round-bottomed flask with condenser was added5-methyl-2-furancarboxylic acid (2.5 g, 19.82 mmol) in Methanol (100mL). H₂SO₄ (10.5 mL, 197 mmol) was added slowly at room temperature. Thereaction mixture was heated to 50° C. overnight. The reaction mixturewas cooled to 0° C. and a saturated solution of NaHCO₃ was added toneutral pH followed by 5N NaOH to pH 10. CHCl₃ was added and the organicphase was separated, dried with Na₂SO₄ and concentrated affording thetitle compound (2.3 g, 16.3 mmol, 82%): LC-MS (ES) m/z=141 (M+H)⁺.

b) methyl 4-bromo-5-methyl-2-furancarboxylate

To a solution of methyl 5-methyl-2-furancarboxylate (2.33 g, 16.29 mmol)and aluminum chloride (3.3 g, 24.75 mmol) in chloroform (50 ml) at roomtemperature was added Br₂ (1.1 ml, 21.35 mmol). The resulting solutionwas stirred at room temperature in a 150 mL sealed tube reactor for 2hours. Upon completion, the solution was cooled in an ice bath, H₂Oadded and reaction partitioned between CHCl₃/H₂O. The organic layer waswashed with NaHCO₃ and then Na₂S₂O₃. The organic layer was dried withNa₂SO₄, concentrated, adsorbed onto silica and purified via columnchromatography (0-20% EtOAc/Hexanes) affording the title compound (2.13g, 9.72 mmol, 60%): LC-MS (ES) m/z=221 (M+H)⁺.

c) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

To a 5 mL sealed flask reactor was added methyl4-bromo-5-methyl-2-furancarboxylate (1.13 g, 5.16 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.31 g, 6.30 mmol) [prepared according to the procedure of Preparation7], K₃PO₄ (3.87 g, 18.23 mmol) and Pd₂(dba)₃ (153 mg, 0.17 mmol) andP(OMe)₃ (32 μL, 0.27 mmol) in 1,4-Dioxane (23 mL). The reaction washeated at 95° C. for 4 hours, cooled to room temperature and partitionedbetween CHCl₃/H₂O. The organic layer was separated, dried with Na₂SO₄,adsorbed onto silica and purified via column chromatography (0-15%EtOAc/Hexanes) affording the title compound (967 mg, 4.39 mmol, 85%):LC-MS (ES) m/z=271 (M+H)⁺.

d) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic Acid

NCS (709 mg, 5.31 mmol) was added in portions to a 150 mL sealed tubereactor containing methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (967 mg, 4.39mmol) in Tetrahydrofuran (THF) (20 mL) at room temperature. The mixturewas heated to 70° C. for 1 hour. 6N NaOH (20 mL, 120 mmol) was thenadded and the mixture stirred at 70° C. for an additional 2 h. Themixture was partitioned between CHCl₃ and H₂O and the pH of the aqueousphase was adjusted to ˜3 with 6N HCl. The organic layer was separated,dried with Na₂SO₄ and concentrated affording the title compound (1.13 g,4.41 mmol, quant.) which was used without further purification: LC-MS(ES) m/z=241 (M+H)⁺.

e)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-furancarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(244 mg, 0.95 mmol),2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(320 mg, 0.95 mmol) [prepared according to the procedure of Preparation6, except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.0 g,17.8 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (533 mg, 1.14 mmol) in chloroform (9 mL). DIEA (830 μL, 4.75mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (242 mg,0.465 mmol, 49%): LC-MS (ES) m/z=521 (M+H)⁺.

f)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-furancarboxamide(238 mg, 0.46 mmol) in Tetrahydrofuran (THF) (3.6 mL) and Methanol (1mL). Hydrazine (100 μL, 3.19 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (157 mg, 0.32 mmol, 71% yield): LC-MS (ES) m/z=391 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3H) 2.91-3.03 (m, 4H) 3.73 (s, 3H)4.36-4.49 (m, 1H) 7.03 (t, J=7.71 Hz, 1H) 7.07-7.14 (m, 2H) 7.29-7.37(m, 1H) 7.39 (s, 1H) 7.67 (s, 1H) 8.14 (s, 3H) 8.65 (d, J=8.59 Hz, 1H).

Example 185

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-Vl)-2-thiophenecarboxamidea) 5-(methyloxy)-2-thiophenecarboxylic Acid

2-(methyloxy)thiophene (1.01 g, 8.85 mmol) was added slowly over 15 minto a 100 mL round-bottomed flask containing 2.5M nBuLi in hexanes (3.8mL, 9.50 mmol) in Tetrahydrofuran (THF) (40 mL) at −78° C. After warmingto room temperature and stirring for 2 h, the mixture was cooled to −35°C. and crushed solid CO₂ was added. The mixture warmed to roomtemperature over 3 hours and was cooled in an ice bath and quenched withNH₄Cl(sat.). The cold reaction mixture was partitioned betweenCHCl₃/H₂O, the aqueous layer was made acidic with 6N HCl. The separatedorganic layer was dried with Na₂SO₄ and concentrated affording the titlecompound (1.3 g, 8.05 mmol, 91%) which was used without furtherpurification: LC-MS (ES) m/z=159 (M+H)⁺.

b) methyl 5-(methyloxy)-2-thiophenecarboxylate

To a 200 mL round-bottomed flask fitted with a condenser was added5-(methyloxy)-2-thiophenecarboxylic acid (1.3 g, 8.22 mmol) in Methanol(40 mL). H₂SO₄ (5 mL, 94 mmol) was added slowly at room temperature andthe reaction stirred at 50° C. overnight. The mixture was cooled to 0°C. and sat. NaHCO₃ was added to neutral pH followed by 5N NaOH to pH 10.The mixture was partitioned between H₂O/CHCl₃ and the organic phase wasseparated and dried over Na₂SO₄. The solution was adsorbed onto silicaand purified via column chromatography (5-50% EtOAc/Hexanes) affordingthe title compound (827 mg, 4.56 mmol, 56%): LC-MS (ES) m/z=173 (M+H)⁺.

c) methyl 4-bromo-5-(methyloxy)-2-thiophenecarboxylate

NBS (903 mg, 5.07 mmol) was added in portions to a 5 mL sealed tubereactor containing methyl 5-(methyloxy)-2-thiophenecarboxylate (0.73 g,4.23 mmol) in N,N-Dimethylformamide (DMF) (20 mL) at room temperatureand the reaction stirred for 1 hour. Additional NBS (249 mg) was addedand after 1 h at room temperature the product was partitioned betweenCHCl₃ and H₂O. The organic layer was dried with Na₂SO₄, adsorbed ontosilica and purified via column chromatography (0-25% EtOAc/Hexanes)affording the title compound (825 mg, 3.19 mmol, 75%): LC-MS (ES)m/z=252 (M+H)⁺.

d) methyl5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 350 mL sealed flask reactor was added methyl4-bromo-5-(methyloxy)-2-thiophenecarboxylate (772 mg, 3.07 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(773 mg, 3.72 mmol) [prepared according to the procedure of Preparation7], K₂CO₃ (1.419 g, 10.27 mmol) and Pd(Pt—Bu₃)₂ (103 mg, 0.20 mmol) in1,4-Dioxane (12 mL) and Water (3 mL). The reaction was heated at 85° C.for 2 hours. The mixture was partitioned between CHCl₃/H₂O and theaqueous layer made acidic with 6N HCl. The separated organic layer wasdried over Na₂SO₄ and evaporated. The resulting material was adsorbedonto silica and purified via column chromatography (0-50% EtOAc/Hexane)affording the title compound (967 mg, 4.39 mmol, 85%): LC-MS (ES)m/z=253 (M+H)⁺.

e) 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a 100 mL round-bottomed flask was added methyl5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (203mg, 0.805 mmol) in Tetrahydrofuran (TH F) (4 mL). 6N NaOH (4 mL, 24.0mmol) was added slowly, the reaction mixture stirred overnight at 70° C.The mixture was neutralized by addition of 6N HCl and partitionedbetween CHCl₃ and H₂O. The layers were separated, the organic layerdried over Na₂SO₄ and concentrated affording the title compound (152 mg,0.64 mmol, 79%), which was used in the next step without furtherpurification: LC-MS (ES) m/z=239 (M+H)⁺.

f)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(148 mg, 0.62 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(242 mg, 0.63 mmol) [prepared according to the procedure of Preparation6] and PyBrop (356 mg, 0.76 mmol) in Chloroform (6 mL). DIEA (550 μL,3.15 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(303 mg, 0.51 mmol, 82%): LC-MS (ES) m/z=569 (M+H)⁺.

g)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was addedN-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(303 mg, 0.51 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (110 μL, 3.50 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (122 mg, 0.23 mmol, 45% yield): LC-MS (ES) m/z=439 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.93-3.02 (m, 1H) 3.03-3.14 (m, 3H) 3.82(s, 3H) 3.98 (s, 3H) 4.41-4.53 (m, 1H) 6.32 (s, 1H) 7.38-7.49 (m, 2H)7.52-7.63 (m, 2H) 7.68 (d, J=7.58 Hz, 1H) 8.01 (s, 1H) 8.17 (s, 3H) 8.93(d, J=8.84 Hz, 1H).

Example 186

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-furancarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(248 mg, 0.97 mmol) [prepared according to the procedure of Example184],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(321 mg, 0.96 mmol) [prepared according to the procedure of Preparation6, except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (557 mg, 1.19 mmol) in chloroform (9.5 mL). DIEA (840 μL,4.81 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(167 mg, 0.26 mmol, 67%): LC-MS (ES) m/z=521 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-furancarboxamide(144 mg, 0.27 mmol) in Tetrahydrofuran (THF) (2.5 mL) and Methanol (1mL). Hydrazine (60 μL, 1.91 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (100 mg, 0.21 mmol, 74% yield): LC-MS (ES) m/z=391 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3H) 2.83-2.93 (m, 2H) 2.94-3.04(m, 2H) 3.73 (s, 3H) 4.32-4.44 (m, 1H) 7.12 (t, J=8.59 Hz, 2H) 7.25-7.33(m, 2H) 7.35 (s, 1H) 7.67 (s, 1H) 8.07 (s, 3H) 8.57 (d, J=8.59 Hz, 1H).

Example 187

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(230 mg, 0.90 mmol) [prepared according to the procedure of Example184],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(348 mg, 0.90 mmol) [prepared according to the procedure of Preparation6, except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (502 mg, 1.07 mmol) in chloroform (8.5 mL). DIEA (790 μL,4.52 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(247 mg, 0.43 mmol, 48%): LC-MS (ES) m/z=571 (M+H)⁺.

b)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide(247 mg, 0.433 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1mL). Hydrazine (95 μL, 3.03 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (206 mg, 0.38 mmol, 88% yield): LC-MS (ES) m/z=441 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.30 (s, 3H) 2.97-3.08 (m, 4H) 3.71 (s, 3H)4.35-4.49 (m, 1H) 7.36 (s, 1H) 7.54 (dt, J=19.20, 7.20 Hz, 3H) 7.62-7.68(m, 2H) 8.14 (s, 3H) 8.65 (d, J=8.84 Hz, 1H).

Example 188

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylicAcid

NCS (382 mg, 2.80 mmol) was added in portions to a 50 mL sealed tubereactor containing methyl5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (642mg, 2.54 mmol) [prepared according to the procedure of Example 185] inTetrahydrofuran (THF) (12 mL) at room temperature. The mixture washeated to 70° C. for 1 hour. The reaction was cooled to roomtemperature, 6N NaOH (10 mL, 60.0 mmol) was added and the mixturestirred an additional 3 h at 70° C. The mixture was partitioned betweenCHCl₃ and H₂O and the aqueous layer was made acidic with 6N HCl. Theorganic layer was dried over Na₂SO₄ and concentrated affording the titlecompound (759 mg, 2.51 mmol, 98%) which was used without furtherpurification: LC-MS (ES) m/z=273 (M+H)⁺.

b)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylicacid (85 mg, 0.31 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(119 mg, 0.31 mmol) [prepared according to the procedure of Preparation6] and PyBrop (180 mg, 0.384 mmol) in chloroform (3.5 mL). DIEA (270 μL,1.54 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(94 mg, 0.14 mmol, 45%): LC-MS (ES) m/z=603 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-2-thiophenecarboxamide(94 mg, 0.16 mmol) in Tetrahydrofuran (THF) (2 mL) and Methanol (1 mL).Hydrazine (35 μL, 1.12 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (27 mg, 0.05 mmol, 31% yield): LC-MS (ES) m/z=473 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.93-3.14 (m, 4H) 3.73 (s, 3H) 4.00 (s, 3H)4.41-4.54 (m, 1H) 7.43 (t, J=7.45 Hz, 1H) 7.57 (ddd, J=14.59, 7.58, 7.39Hz, 2H) 7.62-7.65 (m, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.82-7.89 (m, 1H) 8.12(s, 3H) 8.80 (d, J=9.09 Hz, 1H).

Example 189

Preparation ofN-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 350 mL sealed flask reactor was added methyl4-bromo-5-chloro-2-thiophenecarboxylate (409 mg, 1.60 mmol) [preparedaccording to the procedure of Example 95],1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(388 mg, 1.75 mmol) [prepared according to the procedure of Preparation17], K₂CO₃ (676 mg, 4.89 mmol) and Pd(PtBu₃)₂ (32 mg, 0.06 mmol) in1,4-Dioxane (6 mL) and water (1.5 mL). The reaction was heated at 85° C.for 3 hours. The reaction was partitioned between CHCl₃/H₂O and the pHof the aqueous layer was adjusted to ˜3 with 6N HCl. The separatedorganic layer was dried with Na₂SO₄, adsorbed onto silica and purifiedvia column chromatography (10-65% EtOAc/Hexanes) affording the titlecompound (106 mg, 0.39 mmol, %); LC-MS (ES) m/z=271 (M+H)⁺.

b) 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a 100 mL round-bottomed flask was added methyl5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (106mg, 0.39 mmol) in Tetrahydrofuran (THF) (2 mL). 6N NaOH (2 mL, 12.00mmol) was added slowly and the reaction mixture stirred overnight at 70°C. The reaction was cooled to room temperature, partitioned betweenCHCl₃ and H₂O and the pH of the aqueous layer was adjusted to ˜3 by theaddition of 6N HCl. The layers were separated, the organic layer driedover Na₂SO₄ and concentrated affording the desired compound (96 mg, 0.37mmol, 95%): LC-MS (ES) m/z=257 (M+H)⁺.

c)5-chloro-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (96mg, 0.37 mmol),2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(125 mg, 0.40 mmol) [prepared according to the procedure of Preparation18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol)for 2,6-difluoro-L-phenylalanine] and PyBrop (225 mg, 0.48 mmol) inchloroform (4 mL). DIEA (330 μL, 1.89 mmol) was added and the reactionstirred overnight at room temperature. The mixture was adsorbed ontosilica and purified via column chromatography (25-70% EtOAc/Hex)affording the title compound (98 mg, 0.13 mmol, 34%): LC-MS (ES) m/z=535(M+H)⁺.

d)N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added5-chloro-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(98 mg, 0.18 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL).Hydrazine (40 μL, 1.27 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl3/MeOH/NH4OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (52 mg, 0.10 mmol, 56% yield): LC-MS (ES) m/z=425 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.94 (s, 3H) 2.87-3.09 (m, 4H) 3.69 (s, 3H)4.42 (d, J=6.32 Hz, 1H) 7.10 (ddd, J=12.00, 8.34, 3.41 Hz, 1H) 7.20 (td,J=9.16, 4.67 Hz, 1H) 7.27 (ddd, J=8.97, 5.56, 3.16 Hz, 1H) 7.39 (s, 1H)8.06 (s, 1H) 8.13 (s, 3H) 9.13 (d, J=8.84 Hz, 1H).

Example 190

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylicacid (220 mg, 0.81 mmol) [prepared according to the procedure of Example188],2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(281 mg, 0.84 mmol) [prepared according to the procedure of Preparation6, except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g,17.8 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (472 mg, 1.0 mmol) in Chloroform (8 mL). DIEA (710 μL, 4.07mmol) was added and the reaction stirred overnight at room temperature.The mixture was adsorbed onto silica and purified via columnchromatography (25-70% EtOAc/Hex) affording the title compound (281 mg,0.51 mmol, 63%): LC-MS (ES) m/z=553 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-(methyloxy)-2-thiophenecarboxamide(281 mg, 0.51 mmol) in Tetrahydrofuran (THF) (4.5 mL) and Methanol (1mL). Hydrazine (120 μL, 3.82 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (145 mg, 0.28 mmol, 55% yield): LC-MS (ES) m/z=423 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.86-3.04 (m, 4H) 3.71 (s, 3H) 4.02 (s, 3H)4.31-4.41 (m, 1H) 7.00-7.07 (m, 1H) 7.11 (d, J=7.58 Hz, 2H) 7.28-7.36(m, 1H) 7.64 (s, 1H) 7.73-7.78 (m, 1H) 7.98 (s, 3H) 8.54 (s, 1H).

Example 191

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylicacid (208 mg, 0.76 mmol) [prepared according to the procedure of Example188],2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(257 mg, 0.77 mmol) [prepared according to the procedure of Preparation6, except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g,17.5 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (435 mg, 0.93 mmol) in chloroform (7.6 mL). DIEA (670 μL,3.84 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(238 mg, 0.43 mmol, 56%): LC-MS (ES) m/z=553 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-(methyloxy)-2-thiophenecarboxamide(238 mg, 0.43 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL).Hydrazine (95 μL, 3.03 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (113 mg, 0.22 mmol, 50% yield): LC-MS (ES) m/z=423 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.82-2.92 (m, 2H) 2.93-3.03 (m, 2H) 3.71(s, 3H) 4.02 (s, 3H) 4.26-4.37 (m, 1H) 7.11 (t, J=8.46 Hz, 2H) 7.26-7.32(m, 2H) 7.64 (s, 1H) 7.69-7.84 (m, 1H) 7.95 (s, 3H) 8.45-8.52 (m, 1H).

Example 192

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamidea)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylicacid (210 mg, 0.77 mmol) [prepared according to the procedure of Example188],2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(294 mg, 0.764 mmol) [prepared according to the procedure of Preparation6, except substitutingN-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine(4.98 g, 15.0 mmol) forN-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]and PyBrop (442 mg, 0.94 mmol) in chloroform (7.6 mL). DIEA (670 μL,3.84 mmol) was added and the reaction stirred overnight at roomtemperature. The mixture was adsorbed onto silica and purified viacolumn chromatography (25-70% EtOAc/Hex) affording the title compound(238 mg, 0.43 mmol, 56%): LC-MS (ES) m/z=603 (M+H)⁺.

b)N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(methyloxy)-2-thiophenecarboxamide(203 mg, 0.34 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL).Hydrazine (80 μL, 2.55 mmol) was added and the reaction stirredovernight at room temperature. The mixture was adsorbed onto silica geland purified via column chromatography (90:10:1 CHCl₃/MeOH/NH₄OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess2M HCl in Et₂O and concentrated affording the HCl salt of the titlecompound (86 mg, 0.15 mmol, 44% yield): LC-MS (ES) m/z=473 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.92-3.08 (m, 4H) 3.70 (s, 3H) 4.01 (s, 3H)4.30-4.42 (m, 1H) 7.50-7.60 (m, 3H) 7.61-7.66 (m, 2H) 7.73-7.81 (m, 1H)8.00 (s, 3H) 8.52-8.68 (m, 1H).

Example 193

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) 4-chloro-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of 5-bromo-4-chloro-2-thiophenecarboxylic acid (482 mg, 2mmol) in dioxane/H₂O (4:1, 10 mL) was added1,1′-bis(diphenylphosphino)ferrocenedichloro Palladium (II)dichloromethane complex (16.3 mg, 0.02 mmol), potassium carbonate (828mg, 6 mmol) and5-(5,5-dimethyl-1,3,2-dooxaborinan-2-yl)-1-methyl-1H-pyrazole (832 mg, 4mmol)[prepared according to Preparation 7]. The reaction mixture washeated to 80° C. in a sealed tube for 20 hrs. The reaction mixture waspoured into H₂O (100 mL) and extracted with DCM. The organic layer wasdried over Na₂SO₄, concentrated and purified using silica (EtOAc/hexane(0-45% gradient)) affording the title compound as a white solid (401.7mg, 83%): LC-MS (ES) m/z=243 (M+H)⁺.

b) 4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

A solution of4-chloro-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (121mg, 0.5 mmol) and N-chlorosuccinimide (67 mg, 0.5 mmol) in THF (5 mL)was stirred in a sealed tube at 70° C. After 4 hrs, the solution wasconcentrated and partitioned between DCM and H₂O. The aqueous layer wasextracted several times with DCM. The organic fractions were combined,concentrated and azeotropically dried with toluene to give the titlecompound as a brown oil (136 mg, 98%): LC-MS (ES) m/z=278 (M+H)⁺.

c).4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (136.1 mg, 0.49 mmol),2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(179 mg, 0.51 mmol)[prepared according to Preparation 6],diisopropylethyl amine (260 uL, 1.5 mmol) in DCM (5 mL) was added PyBrop(341 mg, 0.75 mmol) in one portion. After 1 h, the reaction contentswere partitioned between H₂O/DCM. The aqueous phase was washed severaltimes with DCM and the combined organic fractions were dried overNa₂SO₄, concentrated and purified via column chromatography (silica,gradient 0-50% ethyl acetate/hexane) affording the title compound (242mg, 82%) as a white solid: LCMS (ES) m/z=607 (M+H)⁺.

d)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(242 mg, 0.4 mmol) in THF-MeOH (1:1, 4 mL) was added hydrazine (75 uL,2.42 mmol). After 12 h, the solution was concentrated. The resultingresidue was partitioned between DCM and H₂O. The organics were washedthree times with water and acidified to pH˜1 with 6N aqueous HClsolution. The resulting mixture was extracted with water. The aqueousfractions were combined and concentrated to afford the di-HCl salt ofthe desired product as a light yellow solid (77 mg, 40%): LCMS (ES) m/z477 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.08-3.11 (m, 4H) 3.75 (s,3H) 4.50 (br. s., 1H) 7.45 (t, J=6.95 Hz, 1H) 7.55-7.63 (m, 2H) 7.71 (d,J=7.83 Hz, 1H) 7.78 (s, 1H) 8.02-8.10 (m, 3H) 8.12 (s, 1H) 9.12 (d,J=9.09 Hz, 1H)

Example 194

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-chloro-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a light yellow solid according to theprocedure of Example 193, except substituting N-bromosuccinimide (89 mg,0.5 mmol) for and N-chlorosuccinimide: LCMS (ES) m/z 522 (M+H)⁺, ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.0-3.13 (m, 4H) 3.76 (s, 3H) 4.50 (br. s., 1H)7.46 (d, J=7.58 Hz, 1H) 7.55-7.66 (m, 2H) 7.71 (d, J=7.83 Hz, 1H) 7.78(s, 1H) 8.04 (br. s., 4H).

Example 195

Preparation of N-[(1S)-2-amino-1-(3-pyridinylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a light yellow solid according to theprocedure of Example 6, except substituting4-bromo-2-thiophenecarboxylic acid (62 mg, 0.3 mmol) for5-bromo-2-thiophenecarboxylic acid and substituting2-[(2S)-2-amino-3-(3-pyridinyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl(84 mg, 0.3 mmol)[prepared according to Preparation 19] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl:LC-MS (ES) m/z=342 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ ppm 3.17 (dd,J=13.89, 10.86 Hz, 1H) 3.33-3.36 (m, 2H) 3.36-3.44 (m, 1H) 3.96 (s, 3H)4.70 (dd, J=14.02, 6.19 Hz, 1H) 6.47 (s, 1H) 7.51 (s, 1H) 7.88 (d,J=1.26 Hz, 1H) 7.94 (s, 1H) 8.02 (t, J=6.32 Hz, 1H) 8.61 (d, J=7.83 Hz,1H) 8.76 (br. s., 1H) 8.89 (br. s., 1H).

Example 196

Preparation ofN-[(1R)-2-amino-1-phenylethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 20, except substituting4-bromo-2-thiophenecarboxylic acid (83 mg, 0.4 mmol) for4,5-dibromo-2-thiophenecarboxylic acid and substituting1,1-dimethylethyl[(2R)-2-amino-2-phenylethyl]carbamate (94 mg, 0.4 mmol)[prepared according to the procedure of Preparation 1] for1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z=327(M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ ppm 3.44 (d, J=4.29 Hz, 1H) 3.63 (br.s., 1H) 4.18 (s, 3H) 5.47 (dd, J=10.36, 4.55 Hz, 1H) 6.88 (d, J=2.78 Hz,1H) 7.38 (d, J=7.07 Hz, 1H) 7.44 (t, J=7.33 Hz, 2H) 7.55 (d, J=7.83 Hz,2H) 8.08 (d, J=2.53 Hz, 1H) 8.18 (d, J=1.26 Hz, 1H) 8.42 (d, J=1.26 Hz,1H).

Example 197

Preparation ofN-[(1S)-2-amino-1-phenylethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 20, except substituting4-bromo-2-thiophenecarboxylic acid (83 mg, 0.4 mmol) for4,5-dibromo-2-thiophenecarboxylic acid and substituting1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate (94 mg, 0.4 mmol)[prepared according to the procedure of Preparation 1] for1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 327(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.44 (d, J=2.78 Hz, 1H) 3.60 (br.s., 1H) 4.06 (br. s., 3H) 5.47 (dd, J=10.36, 4.29 Hz, 1H) 6.70 (br. s.,1H) 7.38 (d, J=6.82 Hz, 1H) 7.44 (t, J=7.20 Hz, 2H) 7.53 (d, J=7.58 Hz,2H) 7.79 (br. s., 1H) 8.04 (br. s., 1H) 8.32 (br. s., 1H).

Example 198

Preparation ofN-[(1S)-2-amino-1-phenylethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-methyl-2-thiophenecarboxylate (2 g, 8.51mmol)[prepared in Preparation 10], potassium carbonate (5.88 g, 42.5mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.12 g, 10.21 mmol)[prepared according to Preparation 7] andbis(tri-t-butylphosphine)palladium(0) (0.22 g, 0.43 mmol) in 1,4-Dioxane(35 ml) and H₂O (7 ml) was stirred at 80° C. in a sealed tube for 1 h.The reaction mixture was then partitioned between H₂O-DCM and theaqueous phase was washed several times with DCM. The combined organicfractions were dried over Na₂SO₄, concentrated and purified via columnchromatography (silica, 25% EtOAc in hexanes) affording methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate. Thisreaction was run in several batches (1 g, 3×2 g) which were combined forworkup and purification affording the title compound (5.5 g, 78%combined yield) as a viscous yellow oil: LC-MS (ES) m/e 236 (M+H)⁺.

b) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of methyl5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (94 mg, 0.4mmol) in 6N sodium hydroxide (0.67 ml, 4 mmol) and tetrahydrofuran (4ml) was stirred at 70° C. in a sealed tube for 1 h. The resultingsolution was cooled and then partitioned between H₂O-DCM. The aqueousphase was adjusted to pH˜3 and then washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄ and concentratedaffording the desired product (67 mg, 0.3 mmol, 75% yield) as a yellowoil: LC-MS (ES) m/e 223 (M+H)⁺.

c)1,1-dimethylethyl[(2S)-2-({[5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate

To a solution of5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (67 mg,0.3 mmol), 1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate (71mg, 0.3 mmol) [prepared according to the procedure of Preparation 1] anddiisopropylethylamine (0.16 ml, 0.9 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (210 mg, 0.45mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen partitioned between H₂O-DCM. The aqueous phase was washed severaltimes with DCM and the combined organic fractions were dried overNa₂SO₄, concentrated and purified via column chromatography (silica,30-70% EtOAc in hexanes) yielding the title compound (87 mg, 0.2 mmol,65% yield) as a yellow foam: LC-MS (ES) m/e 441 (M+H)⁺.

d).N-[(1S)-2-amino-1-phenylethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of1,1-dimethylethyl[(2S)-2-({[4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate(87 mg, 0.2 mmol) in DCM (2 mL) was added 4N HCl solution in dioxane(0.5 mL, 2 mmol) which stirred at ambient temperature for 15 h. Thesolution was extracted with water three times. The aqueous fractionswere combined and concentrated to afford the di-HCl salt of the titlecompound as a white solid (26 mg, 0.06 mmol, 32%): LC-MS (ES) m/z 341(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.49 (br. s., 3H) 3.43 (d, J=4.80Hz, 1H) 3.55 (d, J=10.36 Hz, 1H) 3.95 (s, 3H) 5.41-5.43 (m, 1H) 6.66 (d,J=2.27 Hz, 1H) 7.38 (d, J=7.07 Hz, 1H) 7.44 (t, J=7.33 Hz, 2H) 7.48-7.53(m, 2H) 7.94-8.02 (m, 2H).

Example 199

Preparation ofN-[(1S)-2-amino-1-phenylethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 24, except substituting5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (89 mg,0.4 mmol) [prepared according to Example 198] for4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (94 mg, 0.4 mmol)[prepared according to the procedure of Preparation 1] for1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 375(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.38-2.41 (m, 1H), 3.38 (d, J=1.52Hz, 1H) 3.49 (d, J=10.86 Hz, 1H) 3.73 (br. s., 3H) 5.41 (d, J=3.54 Hz,1H) 7.30-7.50 (m, 5H) 7.54-7.62 (m, 1H) 7.81 (br. s., 1H).

Example 200

Preparation ofN-[(1S)-2-amino-1-phenylethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 24, except substituting5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (168mg, 0.5 mmol) [prepared according to Example 198] for4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid,N-bromosuccinimide (88.5 mg, 0.5 mmol) for N-chlorosuccinimide and1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (71 mg, 0.3 mmol)[prepared according to the procedure of Preparation 1] for1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 341(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.39 (d, J=4.04 Hz, 3H) 3.42 (br.s., 1H) 3.55 (br. s., 1H) 3.75-3.78 (m, 3H) 5.45 (m, 1H) 7.37 (d, J=7.07Hz, 1H) 7.40-7.46 (m, 2H) 7.49 (br. s., 2H) 7.59-7.68 (m, 1H) 7.80-7.88(m, 1H).

Example 201

Preparation ofN-[(1S)-2-amino-1-phenylethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea) methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (2.56 g,10.00 mmol)[prepared according to Example 95],5-(5,5-dimethyl)-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (3.88 g,20.0 mmol)[prepared according to Preparation 7], potassium carbonate(4.15 g, 30.0 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane complex (0.073 g, 0.1 mmol) in1,4-Dioxane (12 mL) and water (3.00 mL) were heated at 80° C. in asealed tube. After 3 hrs, another batch of5-(5,5-dimethyl)-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.94 g,10.0 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.073 g, 0.1 mmol) were added. After 2 hr,the mixture was concentrated and purified by silica gel eluting with0-35% ethyl acetate/hexane affording the title compound as a yellowsolid (1.74 g, 3.35 mmol, 34%): LC-MS (ES) m/z 257 (M+H)⁺.

b) 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

A solution of methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (304 mg,1.18 mmol) in 6N sodium hydroxide (2 ml, 12 mmol) and Tetrahydrofuran(10 ml) was stirred at 70° C. in a sealed tube for 1 h. The resultingsolution was cooled and then partitioned between H₂O-DCM. The aqueousphase was adjusted to pH˜3 and then washed several times with DCM. Thecombined organic fractions were dried over Na₂SO₄ and concentratedaffording the desired product (276 mg, 1.14 mmol, 96% yield) as a yellowoil: LC-MS (ES) m/e 244 (M+H)⁺.

c)1,1-dimethylethyl[(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate

To a solution of5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (60 mg,0.25 mmol), 1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate (58mg, 0.25 mmol) [prepared according to the procedure of Preparation 1]and diisopropylethylamine (0.12 ml, 0.75 mmol) in DCM at 25° C. wasadded bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (190 mg,0.41 mmol) in one portion. The solution stirred at 25° C. for 12 h andwas then partitioned between H₂O-DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding the title compound (90 mg,0.20 mmol, 79% yield) as a colorless oil: LC-MS (ES) m/e 461 (M+H)⁺.

d).N-[(1S)-2-amino-1-phenylethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of1,1-dimethylethyl[(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate(90 mg, 0.20 mmol) in DCM (2 mL) was added 4N HCl solution in dioxane(0.5 mL, 2 mmol). After 15 h, the solution was extracted with waterthree times. The aqueous fractions were combined and concentrated toafford the di-HCl salt of the title compound as a white solid (63 mg,0.14 mmol, 74%): LC-MS (ES) m/z 361 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm3.41 (dd, J=13.01, 4.17 Hz, 1H) 3.63 (d, J=10.86 Hz, 1H) 4.08 (s, 3H)5.45 (dd, J=10.48, 4.17 Hz, 1H) 6.87 (d, J=2.27 Hz, 1H) 7.36 (d, J=7.33Hz, 1H) 7.42 (t, J=7.33 Hz, 2H) 7.54 (d, J=7.07 Hz, 2H) 8.14 (d, J=2.27Hz, 1H) 8.27 (s, 1H).

Example 202

Preparation ofN-[2-amino-1-(4-fluorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 201, except substituting1,1-dimethylethyl[2-amino-2-(4-fluorophenyl)ethyl]carbamate (63 mg, 0.25mmol) [prepared according to the procedure of Preparation 16] for1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate: LC-MS (ES)m/z=379 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ ppm 3.40 (dd, J=13.01, 4.42Hz, 1H) 3.66 (d, J=2.02 Hz, 1H) 4.03-4.15 (m, 3H) 5.46 (dd, J=10.36,4.29 Hz, 1H) 6.84 (d, J=2.53 Hz, 1H) 7.15 (t, J=8.72 Hz, 2H) 7.60 (dd,J=8.59, 5.05 Hz, 2H) 8.10 (d, J=2.53 Hz, 1H) 8.29 (s, 1H).

Example 203

Preparation ofN-[2-amino-1-(4-chlorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 201, except substituting1,1-dimethylethyl[2-amino-2-(4-chlorophenyl)ethyl]carbamate (45 mg, 0.17mmol) [prepared according to the procedure of Preparation 16] for1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate: LC-MS (ES)m/z=396 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ ppm 3.40 (d, J=4.55 Hz, 1H)3.58 (d, J=10.36 Hz, 1H) 3.98 (s, 3H) 5.41 (d, J=4.55 Hz, 1H) 6.71 (s,1H) 7.43 (dt, J=4.74, 2.31 Hz, 2H) 7.47-7.56 (m, 2H) 7.92 (br. s., 1H)8.13 (s, 1H).

Example 204

Preparation ofN-[2-amino-1-(3-chlorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 201, except substituting1,1-dimethylethyl[2-amino-2-(3-chlorophenyl)ethyl]carbamate (67 mg, 0.25mmol) [prepared according to the procedure of Preparation 16] for1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate: LC-MS (ES)m/z=396 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ ppm 3.41 (dd, J=12.76, 4.93Hz, 5H) 3.36-3.47 (m, 3H) 3.63 (s, 2H) 3.59 (d, J=10.61 Hz, 6H) 3.95 (s,9H) 4.02 (d, J=3.03 Hz, 15H) 5.41 (dd, J=9.09, 3.79 Hz, 8H) 6.67 (d,J=2.27 Hz, 3H) 6.78 (br. s., 4H) 7.33-7.49 (m, 23H) 7.56 (br. s., 7H)8.06 (br. s., 8H) 8.16 (d, J=16.93 Hz, 6H).

Example 205

Preparation ofN-[2-amino-1-(2-chlorophenyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 201, except substituting1,1-dimethylethyl[2-amino-2-(2-chlorophenyl)ethyl]carbamate (67 mg, 0.25mmol) [prepared according to the procedure of Preparation 16] for1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate: LC-MS (ES)m/z=396 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ ppm 3.39 (br. s., 1H) 3.56 (d,J=10.86 Hz, 1H) 4.05 (d, J=3.03 Hz, 3H) 5.87 (dd, J=10.74, 3.41 Hz, 1H)6.81 (br. s., 1H) 7.39 (br. s., 2H) 7.50 (d, J=6.57 Hz, 1H) 7.70 (d,J=7.07 Hz, 1H) 8.04 (br. s., 1H) 8.26 (br. s., 1H).

Example 206

Preparation ofN-[2-amino-1-(4-fluorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[2-({[4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-(4-fluorophenyl)ethyl]carbamate

To a solution of4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (67 mg, 0.24 mmol) [prepared according to Example 193],1,1-dimethylethyl[2-amino-2-(4-fluorophenyl)ethyl]carbamate (61 mg, 0.24mmol) [prepared according to the procedure of Preparation 16],diisopropylethyl amine (126 uL, 0.72 mmol) in DCM (5 mL) was addedPyBrop (168 mg, 0.36 mmol) in one portion. After 1 h, the reactioncontents were partitioned between H₂O/DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, gradient 0-50% ethyl acetate/hexane) affording the titlecompound (93 mg, 0.18 mmol, 76%) as a white solid: LCMS (ES) m/z=514(M+H)⁺.

b).N-[2-amino-1-(4-fluorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of1,1-dimethylethyl[2-({[4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-(4-fluorophenyl)ethyl]carbamate(90 mg, 0.17 mmol) in DCM (2 mL) was added 4N HCl solution in dioxane(0.43 mL, 1.75 mmol). After 15 h, the solution was extracted with waterthree times. The aqueous fractions were combined and concentrated toafford the di-HCl salt of the title compound as a white solid (39.6 mg,0.09 mmol, 52%): LC-MS (ES) m/z 414 (M+H)⁺, ¹HNMR (400 MHz, MeOD) δ ppm3.42 (d, J=2.78 Hz, 1H) 3.56 (br. s., 1H) 3.79 (s, 3H) 5.43 (dd,J=10.23, 4.67 Hz, 1H) 7.11-7.22 (m, 2H) 7.49-7.57 (m, 2H) 7.60 (s, 1H)7.93 (br. s., 1H).

Example 207

Preparation ofN-[(1S)-2-amino-1-phenylethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 206, except substituting1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate (57 mg, 0.24mmol) [prepared according to the procedure of Preparation 1] for1,1-dimethylethyl[2-amino-2-(4-fluorophenyl)ethyl]carbamate: LC-MS (ES)m/z 396 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.42 (br. s., 1H) 3.57 (d,J=11.12 Hz, 1H) 3.80 (s, 3H) 5.44 (dd, J=10.36, 4.29 Hz, 1H) 7.37 (d,J=2.53 Hz, 1H) 7.40-7.47 (m, 2H) 7.48-7.55 (m, 2H) 7.60 (s, 1H) 7.95(br. s., 1H).

Example 208

PreparationN-[(1S)-2-amino-1-phenylethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamidea) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylicAcid

To a solution of methyl5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg,1.169 mmol)[prepared according to the procedure of Example 193] in THF(10 ml) was added N-bromosuccinimide (212 mg, 1.19 mmol). The mixturewas sealed and heated at 70° C. After 2 h, a solution of 6N NaOH (2.0ml, 6.0 M, 11.84 mmol) was added in one portion. The resulting mixturestirred for an additional 2 h and was partitioned between DCM-H₂O. ThepH of the aqueous phase was adjusted to ˜3 and extracted several timeswith DCM. The combined organic fractions were dried over Na₂SO₄,concentrated affording the title compound as a colorless oil (105 mg,28%): LC-MS (ES) m/z=322 (M+H)⁺.

b)1,1-dimethylethyl[(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate

To a solution of4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid(80 mg, 0.25 mmol),1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate (59 mg, 0.25mmol) [prepared according to the procedure of Preparation 1],diisopropylethyl amine (128 uL, 0.75 mmol) in DCM (5 mL) was addedPyBrop (168 mg, 0.36 mmol) in one portion. After 3 h, the reactioncontents were partitioned between H₂O/DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, gradient 0-50% ethyl acetate/hexane) affording the titlecompound (110 mg, 0.18 mmol, 73%) as a white solid: LCMS (ES) m/z=540(M+H)⁺.

c).N-[(1S)-2-amino-1-phenylethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a solution of1,1-dimethylethyl[(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate(81 mg, 0.15 mmol) in DCM (2 mL) was added 4N HCl solution in dioxane(0.38 mL, 1.5 mmol) After 15 h, the solution was extracted with waterthree times. The aqueous fractions were combined and concentrated toafford the di-HCl salt of the title compound as a white solid (18.3 mg,0.04 mmol, 26%): LC-MS (ES) m/z 440 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm3.40 (d, J=13.89 Hz, 1H) 3.60 (br. s., 1H) 3.80 (br. s., 3H) 5.38-5.50(m, 1H) 7.37 (d, J=7.33 Hz, 1H) 7.43 (t, J=7.45 Hz, 2H) 7.52 (d, J=7.58Hz, 2H) 7.61 (s, 1H) 8.02 (br. s., 1H)

Example 209

PreparationN-[2-amino-1-(2-chlorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 206, except substituting1,1-dimethylethyl[2-amino-2-(3-chlorophenyl)ethyl]carbamate (67 mg, 0.25mmol) [prepared according to the procedure of Preparation 16] for1,1-dimethylethyl[2-amino-2-(4-fluorophenyl)ethyl]carbamate: LC-MS (ES)m/z 430 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.45 (d, J=5.56 Hz, 2H)3.72-3.81 (m, 3H) 5.86 (dd, J=9.22, 4.42 Hz, 1H) 7.41 (d, J=2.02 Hz, 2H)7.48-7.55 (m, 1H) 7.58 (br. s., 2H) 7.83 (s, 1H)

Example 210

PreparationN-[2-amino-1-(3-chlorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 206, except substituting1,1-dimethylethyl[2-amino-2-(3-chlorophenyl)ethyl]carbamate (67 mg, 0.25mmol) [prepared according to the procedure of Preparation 16] for1,1-dimethylethyl[2-amino-2-(4-fluorophenyl)ethyl]carbamate: LC-MS (ES)m/z 430 (M+H)⁺, 1 HNMR (400 MHz, MeOD) δ ppm 3.44 (d, J=3.54 Hz, 1H)3.55 (d, J=10.61 Hz, 1H) 3.80 (s, 3H) 5.42 (dd, J=10.36, 4.29 Hz, 1H)7.35-7.49 (m, 3H) 7.55 (s, 1H) 7.59 (s, 1H) 7.95 (d, J=14.40 Hz, 1H)

Example 211

PreparationN-(2-aminoethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 206, except substituting 1,1-dimethylethyl(2-aminoethyl)carbamate (58 mg, 0.36 mmol) for1,1-dimethylethyl[2-amino-2-(4-fluorophenyl)ethyl]carbamate: LC-MS (ES)m/z 320 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.17 (d, J=5.81 Hz, 2H)3.66 (br. s., 2H) 3.78 (s, 3H) 7.60 (s, 1H) 7.66 (s, 1H)

Example 212

PreparationN-[2-amino-1-(4-chlorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 206, except substituting1,1-dimethylethyl[2-amino-2-(4-chlorophenyl)ethyl]carbamate (65 mg, 0.24mmol) [prepared according to the procedure of Preparation 16] for1,1-dimethylethyl[2-amino-2-(4-fluorophenyl)ethyl]carbamate: LC-MS (ES)m/z 431 (M+H)⁺, 1 HNMR (400 MHz, MeOD) δ ppm 3.43 (d, J=4.55 Hz, 1H)3.53 (d, J=10.11 Hz, 1H) 3.79 (s, 3H) 5.43 (dd, J=10.36, 4.55 Hz, 1H)7.43-7.47 (m, 2H) 7.48-7.53 (m, 2H) 7.60 (s, 1H) 7.94 (s, 1H)

Example 213

PreparationN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 99, except substituting2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (73 mg,0.25 mmol) [prepared according to the procedure of Preparation 6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 375 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 0.91-0.99 (m,1H), 1.01-1.10 (m., 1H) 1.39-1.47 (m., 3H) 1.37-1.48 (m, 2H) 1.65-1.77(m, 5H) 1.89 (br. s., 1H) 2.10 (s, 3H) 2.45 (s, 3H) 3.07-3.16 (m, 2H)3.91-3.98 (m, 3H) 4.42 (br. s., 1H) 7.91 (br. s., 1H) 8.24 (s, 1H)

Example 214

PreparationN-[(1S)-2-amino-1-phenylethyl]-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamidea)1,1-dimethylethyl[(2S)-2-({[4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate

To a solution of5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid (110 mg, 0.4 mmol) [prepared in Experiment 99],2-[(2S)-2-amino-4-methylpentyl]-1H-isoindole-1,3(2H)-dione (99 mg, 0.4mmol) [prepared according to the procedure of Preparation 1] anddiisopropylethylamine (0.2 ml, 1.2 mmol) in DCM at 25° C. was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (280 mg, 0.6mmol) in one portion. The solution stirred at 25° C. for 12 h and wasthen partitioned between H₂O-DCM. The aqueous phase was washed severaltimes with DCM and the combined organic fractions were dried overNa₂SO₄, concentrated and purified via column chromatography (silica,30-70% EtOAc in hexanes) yielding the title compound (113 mg, 0.22 mmol,56% yield) as a colorless oil: LC-MS (ES) m/e 506 (M+H)+.

d).N-[(1S)-2-amino-1-phenylethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of1,1-dimethylethyl[(2S)-2-({[4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate(99 mg, 0.22 mmol) in DCM (2 mL) was added 4N HCl solution in dioxane(0.5 mL, 2 mmol). After 15 h, the solution was extracted with waterthree times. The aqueous fractions were combined and concentrated toafford the di-HCl salt of the title compound as an off-white solid (40mg, 0.11 mmol, 52%): LC-MS (ES) m/z 355 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δppm 1.99-2.14 (m, 3H) 2.43 (s, 3H) 3.39 (d, J=9.85 Hz, 1H)) 3.60 (d,J=9.85 Hz, 1H) 3.92 (br. s., 3H) 5.44 (d, J=8.84 Hz, 1H) 7.36 (d, J=2.53Hz, 1H) 7.43 (t, J=5.94 Hz, 2H) 7.49-7.57 (m, 2H) 8.03 (br. s., 1H) 8.14(br. s., 1H).

Example 215

PreparationN-[(1S)-2-amino-1-methylethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 106, except substituting2-[(2S)-2-aminopropyl]-1H-isoindole-1,3(2H)-dione (74 mg, 0.36 mmol) for2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione: LC-MS(ES) m/z 333 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 1.37 (d, J=6.82 Hz,3H) 3.11-3.14 (m, 2H) 3.79 (s, 3H) 4.38-4.40 (m, 1H) 7.60 (br. s., 1H)7.83 (d, J=2.27 Hz, 1H).

Example 216

PreparationN-{(1S)-2-amino-1-[3-(trifluoromethyl)phenyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 100, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(348 mg, 1.0 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 471 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 1.24 (t, J=7.33Hz, 3H) 2.54 (d, J=8.84 Hz, 2H) 2.74 (q, J=7.24 Hz, 2H) 3.05-3.16 (m,1H) 3.26 (d, J=4.80 Hz, 1H) 3.66-3.79 (m, 3H) 4.54 (br. s., 1H)7.47-7.56 (m, 2H) 7.57-7.76 (m, 4H).

Example 217

PreparationN-[(1S)-1-(aminomethyl)-3-methylbutyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 106, except substituting2-[(2S)-2-amino-4-methylpentyl]-1H-isoindole-1,3(2H)-dione (99 mg, 0.4mmol) for2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione: LC-MS(ES) m/z 376 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 0.99 (t, J=6.44 Hz,6H) 1.42 (s, 1H) 1.63-1.80 (m, 2H) 3.04 (br. s., 1H) 3.14 (d, J=3.54 Hz,1H) 3.80 (s, 3H) 4.42 (br. s., 1H) 7.59 (s, 1H) 7.84 (d, J=6.06 Hz, 1H).

Experiment 218

PreparationN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamidea) methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

To a solution of methyl5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (600 mg,2.40 mmol) [prepared according to Example 98] in Tetrahydrofuran (THF)(10 ml) was added N-bromosuccinimide (512 mg, 2.88 mmol). The mixturestirred in a sealed tube at 70° C. for 2 h. The reaction mixture wasthen concentrated and purified with silica gel using a 0-5% gradient(ethyl acetate/hexane) to afford the title compound as an off-whitesolid: LC-MS (ES) m/z 330 (M+H)⁺.

b) methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (635mg, 1.93 mmol), potassium carbonate (1.33 g, 9.64 mmol), PdCl₂(dppf)(141 mg, 0.19 mmol) and trimethylboroxine (0.54 ml, 3.86 mmol) inN,N-dimethylformamide (3 ml) was stirred at 110° C. in a sealed tube for2 h. This reaction mixture was concentrated and partitioned betweenH₂O-DCM. The aqueous phase was washed several times with DCM and thecombined organic fractions were dried over Na₂SO₄, concentrated andpurified via column chromatography (10-50% EtOAc in hexanes) affordingthe title compound (488 mg, 96%) as a yellow oil: LCMS (ES) m/e 265(M+H)⁺.

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic Acid

A solution of methyl4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (488 mg,1.85 mmol) in 6N sodium hydroxide (3.08 ml, 18.5 mmol) andTetrahydrofuran (10 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording the title compound as a yellow foam (448 mg, 1.79mmol, 96% yield) as a yellow oil: LCMS (ES) m/e 251 (M+H)+.

d)4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-ethyl-2-thiophenecarboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (250mg, 1.0 mmol),2-{(2S)-2-amino-3-[4-(fluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(313 mg, 1.05 mmol)[prepared according to the procedure of Preparation6] and diisopropylethylamine (0.52 ml, 3 mmol) in DCM at 25° C. wasadded bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (746 mg,1.6 mmol) in one portion. The solution stirred at 25° C. for 12 h andwas then partitioned between H₂O-DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were driedover Na₂SO₄, concentrated and purified via column chromatography(silica, 30-70% EtOAc in hexanes) yielding the title compound as ayellow solid (490 mg, 0.92 mmol, 92% yield) as a yellow foam: LCMS (ES)m/e 531 (M+H)+.

e)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

To a solution of4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-ethyl-2-thiophenecarboxamide(400 mg, 0.75 mmol) in methanol (8 ml) at 25° C. was added hydrazine(0.12 ml, 3.77 mmol) dropwise. After 12 h, the solution wasconcentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base wastransferred to the HCl salt by addition of excess 4M HCl in dioxane (1ml) to the residue in MeOH (2 ml) affording the HCl salt of the titlecompound as a yellow solid: LC-MS (ES) m/z 401 (M+H)⁺, ¹H NMR (400 MHz,MeOD) δ ppm 1.28 (t, J=7.58 Hz, 3H) 2.07 (s, 3H) 2.75 (m, 2H) 3.02 (d,J=6.32 Hz, 2H) 3.22 (br. s., 2H) 3.92 (d, J=2.27 Hz, 3H) 4.53 (br. s.,1H) 7.02 (t, J=8.59 Hz, 2H) 7.34 (m, 2H), 7.80 (s, 1H) 8.13-8.25 (m,1H).

Example 219

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 103, except substituting2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(332 mg, 1.05 mmol) [Prepared according to the procedure of Preparation6] for 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 391 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.44 (s, 3H)2.91-3.02 (m, 2H) 3.16 (d, J=10.11 Hz, 1H) 3.24 (dd, J=13.14, 3.54 Hz,1H) 3.82 (s, 3H) 4.50 (d, J=3.54 Hz, 1H) 6.44 (d, J=2.02 Hz, 1H)7.05-7.13 (m, 1H) 7.15-7.25 (m, 2H), 7.67-7.70 (m, 2H).

Example 220

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 102, except substituting2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(332 mg, 1.05 mmol) [Prepared according to the procedure of Preparation6] for 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 425 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.40 (s, 3H)2.95-3.03 (m, 2H) 3.23-3.26 (m, 2H) 3.76 (br, s, 3H) 4.96-4.52 (m, 1H),7.07-7.15 (m, 2H) 7.22-7.28 (m, 1H) 7.55-7.77 (m, 2H).

Example 221

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 104, except substituting2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(332 mg, 1.05 mmol) [Prepared according to the procedure of Preparation6] for 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 411 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 3.02 (d, J=7.33Hz, 2H) 3.24 (d, J=6.82 Hz, 2H) 4.01 (d, J=7.58 Hz, 3H) 4.52 (d, J=7.07Hz, 1H) 6.78 (d, J=11.87 Hz, 1H) 7.08-7.21 (m, 1H) 7.26-7.28 (m, 1H)7.94-8.08 (m, 2H).

Example 222

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 106, except substituting2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(332 mg, 1.05 mmol) [Prepared according to the procedure of Preparation6] for 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 446 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.95-3.05 (m,2H) 3.22-3.23 (m, 2H) 3.79 (s, 3H) 4.52 (br. s., 1H) 7.08-7.21 (m, 2H)7.27-7.26 (m, 2H) 7.60 (s, 1H) 7.83 (br. s., 1H)

Example 223

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 99, except substituting2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(332 mg, 1.05 mmol) [prepared according to Preparation 6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 405 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.09 (s, 15H)2.42 (s, 3H) 3.04 (d, J=7.07 Hz, 2H) 3.27 (d, J=4.80 Hz, 2H) 3.88-4.01(m, 3H) 4.54 (br. s., 1H) 7.08-7.21 (m, 2H) 7.29 (d, J=7.58 Hz, 1H) 7.92(br. s., 1H) 8.15-8.26 (m, 1H).

Example 224

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamidea) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol),potassium carbonate (1584 mg, 11.46 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(525 mg, 2.52 mmol)[prepared according to Preparation 7] andbis-(tri-t-butylphosphine)Palladium (0) (58.6 mg, 0.12 mmol) in1,4-dioxane (9.55 ml) and water (1.9 ml) was stirred at 80° C. After 1hr, the solution was partitioned between H₂O-DCM and the aqueous phasewas washed several times with DCM. The combined organic fractions weredried over Na₂SO₄, concentrated and purified via column chromatography(30% EtOAc in hexanes) affording the title compound (124 mg, 0.60 mmol,26% yield) as a white powder: LCMS (ES) m/e 206 (M+H)⁺.

b) methyl5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate(412 mg, 2.0 mmol) and N-chlorosuccinimide (267 mg, 2.0 mmol) in DMF (10mL) was heated at 75° C. for 30 minutes. Another batch ofN-chlorosuccinimide (267 mg, 2.0 mmol) was added. After 1 hr, themixture was concentrated and purified using silica gel and eluting with0-55% ethyl acetate/hexane to afford the title compound as a white solid(225 mg, 0.82 mmol, 71% yield): LCMS (ES) m/e 276 (M+H)⁺.

c) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic Acid

A solution of methyl5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (224mg, 0.82 mmol) in 6N sodium hydroxide (1.36 ml, 8.2 mmol) andtetrahydrofuran (5 ml) was stirred at 70° C. in a sealed tube for 1 h.The resulting solution was cooled and then partitioned between H₂O-DCM.The aqueous phase was adjusted to pH˜4 and then washed several timeswith DCM. The combined organic fractions were dried over Na₂SO₄ andconcentrated affording the title compound (201 mg, 0.77 mmol, 94% yield)as a yellow oil: LCMS (ES) m/e 262 (M+H)⁺.

d)5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide

To a solution of5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid(200 mg, 0.77 mmol)[prepared according to the procedure of Preparation6],2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(254 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.40 ml, 2.30 mmol)in DCM (10 ml) was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (536 mg, 1.15 mmol). After stirring at ambienttemperature for 20 hrs, the mixture was concentrated and purified withsilica gel column eluting with gradient (0-50% ethyl acetate/hexanes) toafford the title compounds as an off-white foamy solid (304 mg, 0.54mmol, 71% yield): LCMS (ES) m/e 560(M+H)+.

e)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide(304 mg, 0.54 mmol) in methanol (5 ml) at 25° C. was added hydrazine(0.08 ml, 2.7 mmol) dropwise. After 12 h, the solution was concentrated,dry loaded onto silica and purified by column chromatography (5% MeOH inDCM (1% NH₄OH)). The free base was converted to the HCl salt by additionof excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml)affording the HCl salt of the title compound as a yellow solid: LC-MS(ES) m/z 430(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.91-3.05 (m, 2H)3.17-3.28 (m, 2H) 3.81 (s, 3H) 4.57 (d, J=9.60 Hz, 1H) 7.12 (br. s., 1H)7.18-7.28 (m., 2H) 7.36-7.39 (m, 1H) 7.58 (s, 1H).

Example 225

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 127, except substituting2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(147 mg, 0.46 mmol) [prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 395 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.90-3.06 (m,2H) 3.18-3.24 (m, 2H) 3.98 (d, J=17.68 Hz, 3H) 4.52-4.64 (m, 1H) 6.67(d, J=1.77 Hz, 1H) 7.19 (dd, J=10.11, 8.59 Hz, 2H) 7.26 (td, J=9.73,2.27 Hz, 1H) 7.51 (d, J=19.96 Hz, 1H) 7.93 (br. s., 1H).

Example 226

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamidea) methyl 4-bromo-5-methyl-2-furancarboxylate

Methyl 4,5-dibromo-2-furancarboxylate (3.7 g, 13.03 mmol) [preparedaccording to Example 127] andtrans-dichlorobis(triphenylphosphine)Palladium (II) (0.46 g, 0.65 mmol)were combined in THF (50 ml) to give a yellow suspension. A THF solutionof methylzinc chloride (11.40 ml, 22.81 mmol) was added dropwise at roomtemperature. After stirring at ambient temperature for 20 h, thesolution was concentrated and purified using silica gel and eluting with0-30% ethyl acetate/hexane to generate the title compound as a whitesolid (1.45 g, 6.61 mmol, 51% yield): LC-MS (ES) m/z 220 (M+H)⁺.

b) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic Acid

To a solution of methyl 4-bromo-5-methyl-2-furancarboxylate (500 mg,2.28 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(950 mg, 4.57 mmol)[prepared according to Preparation 7] and potassiumcarbonate (315 mg, 2.28 mmol) in 1,4-dioxane (8 mL) and water (2.0 mL)was added bis(tri-t-butylphosphine)Palladium (0) (117 mg, 0.23 mmol).The mixture was heated to 80° C. and after 15 h the reaction mixture wasconcentrated. The residue was partitioned between DCM and water. Theorganic layer was concentrated and dissolved in tetrahydrofuran (THF)(8.0 mL). The solution was treated with 6N aqueous solution of sodiumhydroxide (3.80 mL, 22.83 mmol) and heated to 75° C. After 15 h, thereaction mixture was concentrated and partitioned between DCM and water.The aqueous layer was acidified to pH˜3 with 2N HCl aqueous solution andextracted several times with DCM. The organic fractions were combinedand concentrated to afford the title compound as a yellow solid (401 mg,1.95 mmol, 85% yield): LC-MS (ES) m/z 207 (M+H)⁺.

c)N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylicacid (200 mg, 0.97 mmol),2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(322 mg, 1.02 mmol)[prepared according to the procedure of Preparation6] and N,N-diisopropylethylamine (0.51 ml, 2.91 mmol) in DCM (10 ml) wasadded bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (678 mg,1.46 mmol). After stirring at ambient temperature for 20 h, the mixturewas concentrated and purified using silica gel and eluting with a 0-50%ethyl acetate/hexane gradient to afford the title compound as anoff-white foamy solid (181 mg, 0.36 mmol, 37% yield): LCMS (ES) m/e 505(M+H)+.

e)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution ofN-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(176 mg, 0.35 mmol) in methanol (5 ml) at 25° C. was added hydrazine(0.22 ml, 0.7 mmol) dropwise. After 12 h, the solution was concentrated,dry loaded onto silica and purified by column chromatography (5% MeOH inDCM (1% NH₄OH)). The free base was converted to the HCl salt by additionof excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml)affording the HCl salt of the title compound as an off-white solid:

LC-MS (ES) m/z 430(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.91-3.05 (m, 2H)3.17-3.28 (m, 2H) 3.81 (s, 3H) 4.57 (d, J=9.60 Hz, 1H) 7.12 (br. s., 1H)7.18-7.28 (m., 2H) 7.36-7.39 (m, 1H) 7.58 (s, 1H)

Example 227

PreparationN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic Acid

To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylicacid (150 mg, 0.73 mmol)[prepared in Example 126] in THF (10 ml) wasadded N-chlorosuccinimide (97 mg, 0.73 mmol). After stirring at 70° C.for 20 h in a sealed tube, the mixture was partitioned between H₂O-DCMand the pH of the aqueous phase was adjusted to ˜4. The aqueous phasewas washed several times with DCM and the combined organic fractionswere dried over Na₂SO₄ and concentrated affording the title compound asan off-white foamy solid (152 mg, 0.63 mmol, 87% yield): LC-MS (ES) m/z241 (M+H)⁺.

b)4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-furancarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid(150 mg, 0.62 mmol),2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(207 mg, 0.65 mmol)[prepared according to the procedure of Preparation6] and N,N-diisopropylethyl amine (0.33 ml, 1.87 mmol) in DCM (10 ml)was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (436mg, 0.94 mmol). After stirring at ambient temperature for 20 h, themixture was concentrated and purified using silica gel and eluting witha gradient of 0-50% ethyl acetate/hexane to afford the title compound asan off-white foam (200 mg, 0.35 mmol, 57% yield): LC-MS (ES) m/z 539(M+H)⁺.

c)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a solution of4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-furancarboxamide(210 mg, 0.39 mmol) in methanol (5 ml) at 25° C. was added hydrazine(0.02 ml, 0.78 mmol) dropwise. After 12 h, the solution wasconcentrated, dry loaded onto silica and purified by columnchromatography (5% MeOH in DCM (1% NH₄OH)). The free base was convertedto the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to theresidue in MeOH (2 ml) affording the HCl salt of the title compound asan off-white solid: LC-MS (ES) m/z 409(M+H)⁺, ¹H NMR (400 MHz, MeOD) δppm 2.38 (s, 3H) 2.98 (d, J=9.35 Hz, 1H) 3.01 (d, J=5.56 Hz, 1H) 3.23(dd, J=13.01, 8.97 Hz, 2H) 3.73-3.83 (m, 3H) 4.56 (d, J=9.35 Hz, 1H)7.17 (s, 1H) 7.18-7.32 (m, 3H) 7.57 (s, 1H).

Example 228

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 118, except substituting2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(253 mg, 0.8 mmol)[prepared according to the procedure of Preparation 6]for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 409 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.05-2.15 (m,3H) 2.91-3.07 (m, 2H) 3.16-3.26 m., 2H) 3.91 (br. s., 3H) 4.57-4.59 (m.,1H) 7.09-7.31 (m, 3H) 7.51 (br. s., 1H) 8.07 (br. s., 1H)

Example 229

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

The title compound was prepared as a yellow solid according to theprocedure of Example 119, except substituting2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(302 mg, 0.95 mmol)[prepared according to the procedure of Preparation6] for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 389 (M+H)⁺, ¹H NMR (400 MHz, MeOD) δ ppm 2.04-2.15 (m,3H) 2.35-2.47 (m, 3H) 2.99-3.02 (m, 2H) 3.18-3.24 (m, 2H) 3.86-3.96 (m,3H) 4.56-4.62 (m, 1H) 7.16-7.26 (m, 4H) 8.07 (s, 1H).

Example 230N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a solution of4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (220 mg,0.857 mmol) [from Example 92] in DCM (5 mL) at 25° C. was added PyBrOP(440 mg, 0.857 mmol) in one portion, followed by addition of DIPEA (1.5mL, 8.59 mmol). After 10 min, diamine2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(256 mg, 0.857 mmol) was added to above solution. After 2 h, thesolution was concentrated and purified via column chromatography(silica, 20-50% EtOAc/Hexane) affording the title compound (0.39 g, 81%)as a white solid: LC-MS (ES) m/z=537 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

At RT, NH₂NH₂ (0.11 mL, 3.54 mmol) was added to4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(380 mg, 0.708 mmol) in MeOH (4 mL). After 10 h, the solvent was removedunder vacuum to give a residue, which was dissolved in DCM (15 mL), andwashed with H₂O (10 mL×3).

To the above DCM solution was added aqueous HCl (12 N, 2.95 mL, 35.4mmol). After 1 h, the aqueous phase was separated, and washed with DCM(10 ml×3). Water was removed under high vacuum to give the titlecompound (160 mg, 47%) as a white solid: LC-MS (ES) m/z=407 (M+H)⁺, ¹HNMR (d₆-DMSO, 400 MHz) δ ppm 9.18-8.8 (m, 1H), 8.28-8.08 (m, 4H), 8.04(s, 1H), 7.27-7.43 (m, 1), 7.08-7.24 (m, 2H), 6.91-7.08 (m, 1H),4.4-4.34 (m, 1H), 4.14 (q, J=7.3 Hz, 2H), 3.15-2.80 (m, 4H), and 1.29(t, J=7.3 Hz, 3H).

Example 231N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 230, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(339 mg, 0.97 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z=457 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.92 (br s,1H), 7.89-7.80 (m, 1H), 7.63-7.59 (m, 3H), 7.56-7.48 (m, 2H), 4.61-4.53(m, 1H), 4.21-4.15 (m, 2H), 3.46-3.21 (m, 2H), 3.18-3.02 (m, 2H), and1.35 (t, J=7.3 Hz, 3H).

Example 232N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 230, except substituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(584 mg, 1.95 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z=407 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.93 (d,J=1.3 Hz, 1H), 7.85 (d, J=1.3 Hz, 1H), 7.59 (s, 1H), 7.34-7.31 (m, 2H),7.05-7.01 (m, 2H), 4.52 (m, 1H), 4.19 (q, J=7.3 Hz, 2H), 3.26-3.12 (m,2H), 3.05-2.94 (m, 2H), and 1.36 (t, J=7.3 Hz, 3H).

Example 233N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 230, except substituting2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(200 mg, 0.63 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z=425(M+H)⁺, ¹H NMR (d₆-DMSO, 400 MHz) δ ppm 8.88 (d, J=8.3Hz, 1H), 8.16-8.06 (m, 4H), 7.71 (s, 1H), 7.39-7.30 (m, 2H), 7.12 (m,1H), 4.35 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.08-2.87 (m, 4H), and 1.29(t, J=7.1 Hz, 3H).

Example 234N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 93, except substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(149 mg, 0.50 mmol) for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z=582 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 230(b), except substitutingN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(240 mg, 0.41 mmol) for4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide:LC-MS (ES) m/z=452(M+H)⁺, ¹H NMR (d₆-DMSO, 400 MHz) δ ppm 9.24-8.85 (m,1H), 8.26-8.13 (m, 4H), 8.03 (s, 1H), 7.03 (s, 1H), 7.34-7.29 (m, 1H),7.16-7.13 (m, 2H), 7.05-7.00 (m, 1H), 4.39 (m, 1H), 4.14 (q, J=7.3 Hz,2H), 3.06-2.96 (m, 4H), and 1.28 (t, J=7.3 Hz, 3H).

Example 235N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) Methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (300 mg,1.17 mmol) in THF (2 mL) was added Na₂CO₃ (2M, 1.76 mL, 3.52 mmol),Pd(dppf)Cl₂ (86, 0.117 mmol) and1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313mg, 1.41 mmol). The reaction mixture was heated to 80° C. in a sealedtube under N₂. After 2 h, the reaction mixture was concentrated undervacuum and purified on silica (EtOAc/Hex, 20-50%) to afford the titlecompound (0.272 g, 82%) as a light yellow syrup: LC-MS (ES) m/z=271(M+H)⁺.

b) Methyl5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Methyl5-chloro-4-[(1Z)-1-(1-ethyl-2-methylidenehydrazino)-1-propen-1-yl]-2-thiophenecarboxylate(260 mg, 0.96 mmol) and 1-chloro-2,5-pyrrolidinedione (154 mg, 1.15mmol) in THF (4 mL) were heated at 70° C. under N₂ for 2 h, concentratedand purified on silica (EtOAc/Hex, 10-30%) to afford the title compound(0.281 g, 83%) as a syrup: LC-MS (ES) m/z=305 (M+H)⁺.

c) 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

To a solution of methyl5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(260 mg, 0.85 mmol) in THF/H₂O (4 mL/1 mL) was added KOH (478 mg, 8.52mmol). The reaction mixture was heated to 50° C. for 4 h. After themixture was concentrated and diluted with H₂O, the pH was adjusted to 3.The mixture was extracted with DCM (5 mL×3). The collected organiclayers were concentrated under vacuum to give a crude acid, which wasused directly without further purification.

d)5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(˜0.85 mmol) in DCM (5 mL) at 25° C. was added bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP) (477 mg, 1.02 mmol) in oneportion, followed by the addition of DIPEA (0.744 mL, 4.26 mmol). Afterstirring for 10 min, diamine2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(356 mg, 1.02 mmol) was added to the above solution. After 2 h, thesolution was concentrated and purified via column chromatography(silica, 20-50% EtOAc/Hexane) affording the title compound (0.416 g,79%) as a white solid: LC-MS (ES) m/z=621 (M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

5-Chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(410 mg, 0.66 mmol) was dissolved in MeOH (2 mL) and was treated withNH₂NH₂ (1.04 mL, 33 mmol). The reaction was stirred over 5 h at RT,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,95-5%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissolved in water and neutralized by ammonium hydroxide. Themixture was extracted with DCM (5 mL×3), dried over Na₂SO₄ andconcentrated to give a free base of the title compound, which wasdissolved in MeOH (2 mL), and treated with HCl (4 M in dioxane, 1.6 mL).After stirring overnight, the reaction solution was concentrated to givethe title compound (160 mg, 42%) as a di-HCl salt: LC-MS: m/z=491(M+H)⁺, ¹H NMR (d₆-DMSO, 400 MHz) δ ppm 9.34 (J=8.8 Hz, 1H), 8.38-8.03(m, 3H), 7.77 (s, 1H), 7.69-7.59 (m, 2H), 7.53 (dd, J=7.3, 7.3 Hz, 1H),7.42 (dd, J=7.6, 7.6 Hz, 1H), 4.48 (m, 1H), 4.13-4.00 (m, 2H), 3.17-2.90(m, 4H), and 1.29 (m, 3H).

Example 236N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a solution of5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(180 mg, 0.618 mmol) [from Example 235(c)] in DCM (5 mL) at 25° C. wasadded PyBrOP in one portion, followed by addition of DIPEA (0.54 mL,3.09 mmol). After stirring for 10 min,2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(203 mg, 0.68 mmol) was added to above solution in one portion. Afterstirring for 2 h, the solution was concentrated and purified via columnchromatography (silica, 20-50% EtOAc/Hexane) affording the titlecompound (285 mg, 77%) as a white solid: LC-MS (ES) m/z=571 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

At RT, NH₂NH₂ (0.15 ml, 4.78 mmol) was added to5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(280 mg, 0.49 mmol) in MeOH (5 mL). After 10 h the solvent was removedunder vacuum. The resulting residue was dissolved in DCM (15 mL), andwashed with H₂O (10 mL×3). To the DCM solution was added HCl (12 N, 1.0mL). After 1 h, the aqueous phase was separated and washed with DCM (10ml×3). Water was removed under high vacuum to give the tilte compound(179 mg, 67.5%) as an off-white solid: LC-MS (ES) m/z=441 (M+H)⁺, ¹H NMR(d₄-MeOD, 400 MHz) δ ppm 7.72-7.67 (m, 1H), 7.62 (s, 1H), 7.35-7.29 (m,1H), 7.14-7.17 (m, 2H), 7.00-6.96 (m, 1H), 4.53 (m, 1H), 4.14-3.97 (m,2H), 3.37-3.15 (m, 2H), 3.07-2.97 (m, 2H), and 1.33 (t, J=7.1 Hz, 3H).

Example 237N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound (190 mg, 70%) was prepared as an off-white solidaccording to the procedure of Example 236, except substituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(231 mg, 0.77 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 441 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz, no calibration ofchemical shift of MeOD solvent peak) δ ppm 6.09 (s, 1H), 6.08 (s, 1H),5.78-5.75 (m, 2H), 5.53-5.48 (m, 2H), 2.96 (m, 1H), 2.51 (m, 2H),1.71-1.67 (m, 1H), 1.62-1.54 (m, 1H), 1.49-1.38 (m, 2H), and −0.21 (t,J=7.3 Hz, 3H).

Example 238N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound (228 mg, 58.2%) was prepared as an off-white solidaccording to the procedure of Example 236, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(156 mg, 0.45 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 491(M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.66-7.49 (m,6H), 4.60-4.47 (m, 1H), 4.09-4.01 (m, 2H), 3.36-3.18 (m, 2H), 3.16-3.01(m, 2H), and 1.33 (t, J=7.1 Hz, 3H).

Example 239N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxamide

a) methyl 4-bromo-5-iodo-2-thiophenecarboxylate

At −78° C., nBuLi (2.05 mL, 5.13 mmol) was added to a solution of methyl4,5-dibromo-2-thiophenecarboxylate (1.4 g, 4.67 mmol) in THF (10 mL).After the mixture was stirred for 30 min, I₂ (1.185 g, 4.67 mmol) wasadded in 3 mL THF. After the resulting solution was stirred at −78° C.for 1 h, it was quenched with Na₂S₂O₃ at −78° C., and warmed to RT. Thereaction mixture was extracted with DCM, dried over Na₂SO₄, andconcentrated. The crude product was purified on silica (EtOAc/Hex,0-10%) to give the title compound (1.3 g, 56%) as a yellow solid: LC-MS(ES) m/z 348(M+H)⁺.

b) methyl 4-bromo-5-(trifluoromethyl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-5-iodo-2-thiophenecarboxylate (500 mg,1.44 mmol), copper (I) iodide (137 mg, 0.72 mmol) and potassium fluoride(251 mg, 4.32 mmol) in DMF/HMPA (5 ml/5 mL) was added methyldifluoro(fluorosulfonyl)acetate (1.1 g, 5.76 mmol). The mixture washeated at 70° C. under N₂ in a sealed tube. After 1 h, the reaction wasquenched with NH₄Cl (sat'd) (2 mL), extracted with ether (5 mL×5) andwashed with distilled water (5 mL×5). The combined organic phase wasdried over Mg₂SO₄ and purified on silica (EtOAc/Hex, 20-50%) to affordthe title compound (0.82 g) containing a 60% inseparable impurity: LC-MSm/z (ES) 290 (M+H)⁺.

c) methyl4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylate

A mixture of methyl 4-bromo-5-(trifluoromethyl)-2-thiophenecarboxylate(0.8 g, 40% purity, 1.11 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.299 g, 1.434 mmol), tetrakis (0.128 g, 0.11 mmol) and K₂CO₃ (0.459 g,3.32 mmol) in dioxane/H₂O (5 mL/1 mL) was heated to 70° C. in a sealedtube. After 12 h, the reaction mixture was concentrated under vacuum andpurified on silica (EtOAc/Hex, 40-60%) to afford the title compound(0.25 g, 70%) as a light yellow solid: LC-MS (ES) m/z 291 (M+H)⁺.

d)4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylicAcid

To a solution of methyl4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylate(250 mg, 0.77 mmol), in THF/H₂O (3 mL/0.3 mL), was added KOH (217 mg,3.88 mmol). The reaction mixture was heated to 50° C. for 4 h. After themixture was concentrated and diluted with H₂O, the pH was adjusted to 3.The mixture was extracted with DCM (5 mL×3). The collected organiclayers were concentrated under vacuum to give crude acid (235 mg, 80%pure) which was used directly in the next step without furtherpurification: LC-MS (ES) 277 (M+H)⁺.

e)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxamide

At room temperature, a mixture of4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylicacid (235 mg, 80% purity, 0.68 mmol), phosphoniumhexafluorophosphate(PyBrOP) (381 mg, 0.19 mmol), DIPEA (0.59 mL, 3.4 mmol) and2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(261 mg, 0.75 mmol) in DCM (5 mL) was stirred for 2 h. The reactionsolution was concentrated and purified via column chromatography(silica, 20-50% EtOAc/Hexane) affording the title compound (386 mg, 86%)as a white solid: LC-MS (ES) 607 (M+H)⁺

f)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxamide

N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxamide(150 mg, 0.25 mmol) was dissolved in MeOH (5 mL) and was treated withNH₂NH₂ (0.76 mL, 24.2 mmol). The reaction was stirred over 5 h,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,95-5%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissolved in water, and ammonium hydroxide (0.32 mL, 30% wt %,2.46 mmol) was added. The mixture was extracted with DCM (5 mL×3), driedover Na₂SO₄ and concentrated to give a free base of the title compound.The free base compound was dissolved in MeOH (2 mL), and treated withHCl (4 M in dioxane, 0.62 mL, 2.48 mmol). After stirring overnight, thereaction solution was concentrated to give the title compound (90 mg,66%) as a white solid LC-MS (ES) m/z 477 (M+H)⁺, ¹H NMR (d₆-DMSO, 400MHz) δ ppm 8.00 (d, J=1.1 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.72 (d,J=7.8 Hz, 1H), 7.59-7.52 (m, 2H), 7.44 (d, J=7.4 Hz, 1H), 6.57 (d, J=2.0Hz, 1H), 4.67 (m, 1H), 3.87 (s, 3H), and 3.37-3.14 (m, 4H).

Example 240N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a suspension of NaH (4.3 g, 60%, 108 mmol) in THF (200 mL) at RT wasadded 4-methyl-1H-pyrazole (6.8 g, 83 mmol) dropwise. After 30 min, Etl(8.03 mL, 99 mmol) was added dropwise. After the reaction was complete(2 h), the reaction solution was diluted with saturated aqueous NH₄Cland extracted with ether. The ether fractions, were washed with water(3×100 mL), and dried over MgSO₄.

At 0° C., to the above ether solution of 4-methylpyrazole was addedn-BuLi (36.4 mL, 2.5 M in Hexane, 91 mmol) dropwise. The reactionsolution was stirred for 1 hour at RT and then cooled to −78° C. [J.Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.49 g, 99 mmol).After 15 min at −78° C., the reaction was allowed to warm to 0° C. over1 hour. The reaction was diluted with saturated NH₄Cl solution andextracted with DCM. The organics were dried over Na₂SO₄ and concentratedunder vacuum to afford1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(16 g, 80% purity) as a syrup which was used without furtherpurification: LC-MS (ES) m/z 155 (M+H)⁺ for [RB(OH)2].

b) methyl 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A mixture of methyl 4-bromo-2-thiophenecarboxylate (300 mg, 1.36 mmol),1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(449 mg, 1.9 mmol), Pd(Ph₃P)₄ (157 mg, 0.136 mmol), and K₂CO₃ (536 mg,4.07 mmol) was heated at 70° C. for 2 h, concentrated and purified onsilica (EtOAc/Hex, 10-30%) to afford the title compound (0.27 g, 79%) asa syrup: LC-MS m/z=251 (M+H)⁺.

c) 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of methyl4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (270 mg,1.08 mmol) in THF/H₂O (2 mL/0.4 mL) was added KOH (303 mg, 1.79 mmol).The reaction mixture was heated to 50° C. for 4 h. After the mixture wasconcentrated and diluted with H₂O, the pH was adjusted to 3. The mixturewas extracted with DCM (5 mL×3). The collected organic layers wereconcentrated under vacuum to give the crude acid (240 mg), which wasused directly in the next step without further purification: LC-MSm/z=237 (M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a mixture of4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (240 mg,1.02 mmol) and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(Pybrop) (568 mg, 1.22 mmol) was added DIPEA (1.77 ml, 10.16 mmol).After 10 min,2-{(2S,4Z)-2-amino-4-[(1E)-1-(trifluoromethyl)-1-propen-1-yl]-4,6-heptadiene-1-yl}-1H-isoindole-1,3(2H)-dione(425 mg, 1.22 mmol) was added. After 2 h, the solution was concentratedand purified via column chromatography (silica, 20-50% EtOAc/Hexane)affording the title compound (365 mg, 63%) as a white solid: LC-MS (ES)m/z 567 (M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(365 mg, 0.64 mmol) was dissolved in MeOH (8 mL) and was treated withNH₂NH₂ (0.1 mL, 3.22 mmol). The reaction was stirred over 5 h,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,95-5%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissolved in water, and ammonium hydroxide (4.18 mL, 30% wt %,32.2 mmol) was added. The mixture was extracted with DCM (5 mL×3), driedover Na₂SO₄ and concentrated to give a free base of the title compound.The free base compound was dissolved in MeOH (2 mL) and treated with HCl(4 M in dioxane, 3.22 mL, 12.88 mml). After stirring overnight, thereaction solution was concentrated to give the title compound (190 mg,56.7%) as a white solid: LC-MS (ES) m/z 437 (M+H)⁺, NMR (d₆-DMSO, 400MHz) δ ppm 8.96 (m, 1H), 8.17-8.04 (m, 4H), 7.87 (s, 1H), 7.69 (d, J=7.6Hz, 1H), 7.62 (m, 1H), 7.53 (dd, J=7.3, 7.3 Hz, 1H), 7.42 (d, J=7.6 Hz,1H), 7.38 (s, 1H), 4.50 (m, 1H), 4.09 (q, J=7.3 Hz, 2H), 3.18-2.98 (m,4H), 2.00 (s, 3H), and 1.27 (t, J=7.3 Hz, 3H).

Example 241(N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (125 mg,0.53 mmol) [from Example 240(c)] in DCM (5 mL) at 25° C. was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP) in oneportion (350 mg, 0.75 mmol), followed by addition of DIPEA (0.7 ml, 4.0mmol). After 10 min,2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(180 mg, 0.60 mmol) was added to above solution. After 2 h, the reactionmixture was concentrated and purified via column chromatography (silica,20-50% EtOAc/Hexane) affording the title compound (258 mg, 94%) as awhite solid: LC-MS (ES) m/z 517 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

At RT, NH₂NH₂ (0.1 mL, 3.19 mmol) was added toN-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(252 mg, 0.49 mmol) in MeOH (5 ml). After 10 h, the solvent was removedunder vacuum. The resulting residue was dissolved in DCM (10 mL) andwashed with H₂O (10 mL×3).

To the above DCM solution was added HCl (36%, 2 mL). After 1 h, theaqueous phase was separated and washed with DCM (10 ml×3). Water wasremoved under high vacuum to give the title compound (170 mg, 72%) as anoff-white solid: LC-MS (ES) m/z 387 (M+H)⁺, NMR (d₆-DMSO, 400 MHz) δ ppm8.87 (d, J=8.9 Hz, 1H), 8.08 (br s, 2H), 8.01 (s, 1H), 7.08 (s, 1H),7.37 (s, 1H), 7.35-7.29 (m, 1H), 7.16-7.10 (m, 2H), 7.05-7.00 (m, 1H),4.38 (m, 1H), 4.07 (q, J=7.3 Hz, 2H), 3.04-2.94 (m, 4H), 2.00 (s, 3H),and 1.26 (t, J=7.3 Hz, 3H).

Example 242N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound (180 mg, 67%) was prepared as an off-white solidaccording to the procedure of Example 241, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(220 mg, 0.63 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 437 (M+H)⁺, NMR (d₆-DMSO, 400 MHz) δ ppm 8.96 (d, J=8.84Hz, 1H), 8.15 (m, 2H), 8.04 (d, J=1.3 Hz, 1H), 7.86 (d, J=1.3 Hz, 1H),7.69-7.49 (m, 4H), 7.36 (s, 1H), 4.39 (m, 1H), 4.09 (q, J=7.1 Hz, 2H),3.11-3.00 (m, 4H), 1.99 (s, 3H), and 1.25 (t, J=7.1 Hz, 3H).

Example 243N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 241, except substituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(160 mg, 0.536 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 387 (M+H)⁺., NMR (d₆-DMSO, 400 MHz) δ ppm 8.90 (d, J=8.6Hz, 1H), 8.13 (m, 2H), 8.03 (d, J=1.3 Hz, 1H), 7.87 (d, J=1.3 Hz, 1H),7.38-7.30 (m, 3H), 7.12-7.08 (m, 2H), 4.36 (m, 1H), 4.07 (q, J=7.1 Hz,2H), 3.07-2.97 (m, 2H), 2.96-2.88 (m, 2H), 2.00 (s, 3H), and 1.25 (t,J=7.1 Hz, 3H).

Example 244N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound (210 mg, 72%) was prepared as an off-white solidaccording to the procedure of Example 241, except substituting2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(240 mg, 0.76 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 405 (M+H)⁺, NMR (d₆-DMSO, 400 MHz) δ ppm 8.99 (d, J=8.34Hz, 1H), 8.16 (m, 2H), 8.09 (d, J=1.0 Hz, 1H), 7.87 (d, J=1.0 Hz, 1H),7.40-7.30 (m, 3H), 7.13 (br s, 1H), 4.36 (m, 1H), 4.08 (q, J=7.3 Hz,2H), 3.06-2.99 (m, 2H), 2.96-2.33 (m, 2H), 2.00 (s, 3H), and 1.26 (t,J=7.3 Hz, 3H).

Example 245N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) Methyl5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A mixture of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (230 mg, 0.9mmol),1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(425 mg, 1.8 mmol), PdCl₂(dppf) (65.9 mg, 0.09 mmol), and sodiumcarbonate (2N aq, 1.35 mL, 2.7 mmol) in THF (5 mL) was heated to 70° C.in a sealed tube. Afte 5 h, the reaction mixture was concentrated undervacuum and purified on silica (EtOAc/Hex, 40-60%) to afford the titlecompound (241 mg, 92%) as a light yellow solid: LC-MS (ES) m/z=285(M+H)⁺.

b) 5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicAcid

To a solution of methyl5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(260 mg, 0.90 mmol) in THF/H₂O (2 mL/2 mL) was added KOH (201 mg, 3.6mmol). The reaction mixture was heated to 50° C. for 4 h. After themixture was concentrated and diluted with H₂O, the pH was adjusted to 3.The mixture was extracted with DCM (5 mL×3). The collected organiclayers were concentrated under vacuum to give crude5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylicacid, which was used directly without further purification: LC-MS (ES)m/z 271 (M+H)⁺.

c)5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To the above acid in DCM (5 mL) at 25° C. was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (542 mg,1.16 mmol) in one portion, followed by addition of DIPEA (0.16 mL, 0.90mmol). After 10 min,2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(312 mg, 0.90 mmol) was added in one portion. After 2 h, the reactionsolution was concentrated and purified via column chromatography(silica, 20-50% EtOAc/Hexane) affording the title compound (278 mg, 49%for two steps) as a white solid: LC-MS (ES) m/z 601 (M+H)⁺.

d)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

5-Chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(255 mg, 0.42 mmol) was dissolved in MeOH (2 mL) and was treated withNH₂NH₂ (0.13 mL, 4.2 mmol). The reaction was stirred over 5 h,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,95-5%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissolved in water and ammonium hydroxide was added. Themixture was extracted with DCM (5 mL×3), dried over Na₂SO₄ andconcentrated to give a free base of the title compound. The free basecompound was dissolved in MeOH (1 mL) and treated with HCl (4 M indioxane, 2.1 mL). After stirring overnight, the mixture was concentratedto give 120 mg of the title compound (120 mg, 49%) as an off-whitesolid: LC-MS (ES) m/z 471 (M+H)⁺, ¹H NMR (d₄-MeOD, 400 MHz) δ ppm 7.91(br s, 2 h), 7.71 (m, 1H), 7.59 (m, 1H), 7.53 (m, 1H), 7.44 (m, 1H),4.65 (m, 1H), 4.21 (m, 2H), 3.37-3.14 (m, 4H), 2.07 (s, 3H), and 1.40(m, 3H).

Example 246N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a)5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(130 mg, 0.48 mmol) [from Example 245(b)] in DCM (5 mL) at 25° C. wasadded PyBrOP (250 mg, 0.54 mmol) in one portion, followed by addition ofDIPEA (0.7 mL, 4.01 mmol). After 10 min,2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(150 mg, 0.50 mmol) was added to above solution. After 2 h, the reactionmixture was concentrated and purified via column chromatography (silica,20-50% EtOAc/Hexane) affording the title compound (210 mg, 79%) as awhite solid: LC-MS m/z (ES) 551 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

At RT, NH₂NH₂ (0.1 mL, 3.19 mmol) was added to5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(201 mg, 0.36 mmol) in MeOH (3 mL). After 10 h, the solvent was removedunder vacuum. The resulting residue was taken into DCM (10 mL) andwashed with H₂O (10 mL×3). To the DCM solution was added HCl (36%, 2mL). After 1 h, the aqueous phase was separated and washed with DCM (10ml×3). Water was removed under high vacuum to give the title compound(101 mg, 53%) as an off-white solid: LC-MS (ES) m/z 421 (M+H)⁺, ¹H NMR(d₆-DMSO, 400 MHz) δ ppm 9.02 (d, J=8.3 Hz, 1H), 8.08 (s, 2H), 7.97 (s,1H), 7.42 (s, 1H), 7.32 (m, 1H), 7.15-7.09 (m, 1H), 7.06-7.01 (m, 1H),4.35 (m, 1H), 3.95 (m, 2H), 3.05-2.98 (m, 2H), 2.96-2.88 (m, 2H), and1.92 (s, 3H), and 1.24 (t, J=6.6 Hz, 3H).

Example 247N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound (95 mg, 50.2%) was prepared according to theprocedure of Example 246, except substituting2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(152 mg, 0.48 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 439 (M+H)⁺, ¹H NMR (d₆-DMSO, 400 MHz) δ ppm 9.10 (d,J=8.6 Hz, 1H), 8.13 (s, 2H), 8.03 (s, 1H), 7.42 (s, 1H), 7.39-7.30 (m,2H), 7.15-7.10 (m, 1H), 4.33 (m, 1H), 3.95 (m, 2H), 3.05-2.99 (m, 2H),2.96-2.88 (m, 2H), 1.92, and 1.24 (t, J=6.3 Hz, 3H).

Example 248N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-diethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) Methyl 4-(4-ethenyl-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A mixture of methyl4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (200 mg, 0.64mmol), Pd(Ph₃P)₄ (73.3 mg, 0.06 mmol), and tributyl(ethenyl)stannane(302 mg, 0.95 mmol) was heated at 90° C. for 1 h under N₂ in a sealedtube. The mixture was purified on Silica (10%-20% EtOAc in Hex) to givethe title compound (151 mg, 76%): LC-MS (ES) m/z 263 (M+H)⁺.

b) Methyl 4-(1,4-diethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Pd/C (12 mg, 10%) was added to a solution of ethyl4-(4-ethenyl-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (150 mg,0.57 mmol) in EtOH. The air in the system was removed by vacuum. Thereaction mixture was stirred for 10 h under a balloon of hydrogen gas.The reaction was diluted with MeOH (2 mL) and filtered through Celite.Concentration of the reaction solution gave the title compound (149 mg,94%) as a yellow oil: LC-MS (ES) m/z 265 (M+H)⁺.

c)4-(1,4-diethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of methyl4-(1,4-diethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (149 mg, 0.56mmol) in THF/H₂O (5 mL/5 mL) was added KOH (158 mg, 2.82 mmol). Thereaction mixture was heated to 50° C. for 4 h. After the mixture wasconcentrated and diluted with H₂O, the pH was adjusted to 3. The mixturewas extracted with DCM (5 mL×3). The collected organic layers wereconcentrated under vacuum to give a crude acid, which was used directlywithout of further purification: LC-MS (ES) m/z 251 (M+H)⁺.

To the above acid in DCM (5 mL) at 25° C. was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (315 mg,0.68 mmol) in one portion, followed by the addition of DIPEA (0.98 mL,5.64 mmol) and2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(196 mg, 0.56 mmol). After 2 h, the solution was concentrated andpurified via column chromatography (silica, 20-50% EtOAc/Hexane)affording the title compound (0.315 g, 94%) as a white solid: LC-MS (ES)m/z 581 (M+H)⁺.

d)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-diethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(1,4-diethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(310 mg, 0.53 mmol) was dissolved in MeOH (1 mL) and was treated withNH₂NH₂ (0.34 mL, 10.68 mmol). The reaction was stirred over 5 h,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,95-5%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissovled in water (2 mL) and ammonium hydroxide (3.47 mL, 30%,26.7 mmol) was added. The mixture was extracted with DCM (5 mL×3), driedover Na₂SO₄ and concentrated to give a free base of the title compound.The free base was dissolved in MeOH (1 mL) and treated with HCl (4 M indioxane, 2.1 mL). After stirring overnight, the reaction solution wasconcentrated to give the title compound (140 mg, 48%) as an off-whitesolid: LC-MS (ES) m/z 451 (M+H)⁺, ¹H NMR (d₆-DMSO, 400 MHz) δ ppm8.25-8.23 (m, 1H), 8.16-8.14 (m, 1H), 8.10-8.08 (m, 1H), 7.71-7.67 (m,1H), 7.65-7.61 (m, 1H), 7.52-7.47 (m, 1H), 7.44-7.39 (m, 1H), 4.69 (m,1H), 4.45-4.37 (m, 2H), 3.39-3.18 (m, 4H), 2.63-2.55 (m, 2H), 1.49-1.44(m, 3H), and 1.24-1.19 (m, 3H).

Example 249N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Method A:

To a solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (500 mg,1.96 mmol) in THF (10 mL) was added aqueous Na₂CO₃ (2N, 3 mL, 6.0 mmol),PdCl₂(dppf) (143 mg, 0.196 mmol) and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(522 mg, 2.35 mmol). The reaction mixture was heated to 70° C. in asealed tube. After 2 h, the reaction mixture was concentrated undervacuum and purified on silica (EtOAc/Hex, 10-20%) to afford the titlecompound (410 mg, 77%) as a tan solid: LC-MS (ES) m/z 271 (M+H)⁺.

Method B:

To a 250 mL sealed flask was added1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(10.43 g, 47.0 mmol), potassium carbonate (16.23 g, 117 mmol), methyl4-bromo-5-chloro-2-thiophenecarboxylate (10 g, 39.1 mmol) andbis(tri-t-butylphosphine)palladium(0) (1.6 g, 3.13 mmol) in 1,4-dioxane(120 mL) and H₂O (20 ml). After stirring for 90 min at 70° C., thereaction solution was diluted with DCM (100 mL) and washed with H₂O. Theorganic layer was dried Na₂SO₄, filtered and concentrated. The residuewas purified on silica gel (hexanes/EtOAC, 10-30%) to give the titlecompound (7.6 g, 72%) as a tan solid: LC-MS (ES) m/z 271 (M+H)⁺.

b) 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic Acid

To a solution of methyl5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (7.6 g,28.1 mmol) in THF/H₂O (30 mL/5 mL) was added KOH (4.72 g, 84 mmol). Thereaction mixture was heated to 50° C. for 1 h. After the mixture wasconcentrated and diluted with H₂O, the pH was adjusted to 3. The mixturewas extracted with DCM (50 mL×3). The collected organic layers wereconcentrated under vacuum to give the crude acid (6.8 g, 94%), which wasused directly in the next step without further purification: LCMS (ES)m/z 257 (M+H)⁺.

c)5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 500 mL round-bottomed flask was added5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid(6.8 g, 26.5 mmol),2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(8.69 g, 29.1 mmol), N,N-diisopropyl ethylamine (14 mL, 80 mmol) andPybrop (18.52 g, 39.7 mmol) in dichloromethane (DCM) (100 mL). Afterstirring at RT for 1 h, the reaction solution was washed with H₂O (2×100mL) and the organic layer was dried Na₂SO₄, filtered and concentrated.The crude product was added to a silica gel column and was eluted with(EtOAc/hexanes, 1:1) to give the title compound (6.1 g, 42.9%) as awhite solid: LCMS (ES) m/z 537 (M+H)⁺.

d)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

At RT, NH₂NH₂ (4 mL, 127 mmol) was added to5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(5.2 g, 9.68 mmol) in MeOH (30 ml). After 10 h, the solvent was removedunder vacuum. The resulting residue was taken into DCM (200 mL) andwashed with H₂O (50 mL×5).

To the above DCM solution was added HCl (36%, 50 mL, 600 mmol). After 1h, the aqueous phase was separated and washed with DCM (50 ml×5). Waterwas removed under high vacuum to give the title compound (3.8 g, 79%) asa white solid: LC-MS (ES) m/z 407 (M+H)⁺, NMR (d₄-MeOD, 400 MHz) δ ppm8.75 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.85 (m, 1H), 7.34-7.29 (m, 1H),7.15-7.09 (m, 2H), 7.00-6.95 (m, 1H), 4.54 (m, 1H), 3.88 (s, 3H),3.26-3.18 (m, 2H), 3.09-2.98 (m, 2H), and 2.08 (s, 3H).

Example 250N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid (180 mg, 68%) accordingto the procedure of Example 249, except substituting2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(209 mg, 0.6 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 457 (M+H)⁺, NMR (d₄-MeOD, 400 MHz) δ ppm 7.94 (s, 1H),7.90 (s, 1H), 7.65-7.60 (m, 2H), 7.55-7.48 (m, 2H), 4.55 (m, 1), 3.89(s, 3H), 3.37-3.27 (m, 2H), 3.16-3.06 (m, 2H), and 2.08 (s, 3H).

Example 251

N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as white solid (95 mg, 39%) according tothe procedure of Example 249, except substituting2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(584 mg, 1.96 mmol) for2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione:LC-MS (ES) m/z 407 (M+H)⁺, NMR (d₄-MeOD, 400 MHz) δ ppm 7.81 (s, 2H),7.35-7.31 (m, 2H), 7.06-7.01 (m, 2H), 4.51 (m, 1H), 3.89 (s, 3H),3.25-3.16 (m, 2H), 3.05-2.94 (m, 2H), and 2.07 (s, 3H).

Example 252N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) methyl 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

To a solution of methyl 4-bromo-2-furancarboxylate (500 mg, 2.439 mmol)in THF (5 mL) was added aqueous Na₂CO₃ (2N, 3.6 mL, 7.2 mmol),PdCl₂(dppf) (160 mg, 0.22 mmol), and1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(700 mg, 2.96 mmol). The reaction mixture was heated to 70° C. in asealed tube. After 2 h, the reaction mixture was concentrated undervacuum and purified on silica (EtOAc/Hex, 20-40%) to afford the titlecompound (460 mg, 76%) as a light yellow solid: LC-MS (ES) m/z 235(M+H)⁺.

b)N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of methyl4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (210 mg, 0.90mmol) in THF/H₂O (5 mL/0.5 mL) was added KOH (200 mg, 3.56 mmol). Thereaction mixture was heated to 50° C. for 4 h. After the mixture wasconcentrated and diluted with H₂O (2 mL), the pH was adjusted to 3. Themixture was extracted with DCM (5 mL×3). The collected organic layerswere concentrated under vacuum to give a crude acid, which was useddirectly in the next step without further purification: LC-MS (ES) m/z221 (M+H)⁺.

To the crude 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acidin DCM (5 mL) at 25° C. was added PyBrOP (370 mg, 0.79 mmol) in oneportion, followed by the addition of DIPEA (0.8 mL, 4.58 mmol). After 10min,2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(220 mg, 0.74 mmol) was added to the reaction solution. After 2 h, thereaction mixture was concentrated and purified via column chromatography(silica, 20-50% EtOAc/Hexane) affording the title compound (164 mg, 54%)as a white solid: LC-MS (ES) m/z 501 (M+H)⁺.

c)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

At RT, NH₂NH₂ (0.1 mL, 3.19 mmol) was added to a solution ofN-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxamide(150 mg, 0.3 mmol) in MeOH (5 mL). After 10 h, the solvent was removedunder vacuum. The resulting residue was taken into DCM (10 mL) andwashed with H₂O (10 mL×3).

To the DCM solution was added HCl (36%, 1 mL, 12 mmol). After 1 h, theaqueous phase was separated, and washed with DCM (10 ml×3). Water wasremoved under high vacuum to give the title compound (80 mg, 57%) as anoff-white solid: LC-MS (ES) m/z 371 (M+H)⁺, NMR (d₄-MeOD, 400 MHz) δ ppm8.19 (s, 1H), 8.05 (s, 1H), 7.44 (s, 1H), 7.32 (m, 1H), 7.16-7.08 (m,2H), 6.97 (m, 1H), 4.62 (m, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.38-3.18 (m,2H), 3.10-2.99 (m, 2H), 2.15 (s, 3H), and 1.46 (t, J=7.1 Hz, 3H).

Example 253N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) methyl 4-(1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate

To a solution of methyl 4-bromo-2-furancarboxylate (1.0 g, 4.88 mmol) inTHF (20 mL) was added aqueous Na₂CO₃(2N, 8 mL, 16 mmol.), PdCl₂(dppf)(0.35 g, 0.49 mmol) and1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3g, 5.85 mmol). The reaction mixture was heated to 70° C. in a sealedtube. After 2 h, the reaction mixture was concentrated under vacuum andpurified on silica (EtOAc/Hex, 20-40%) to afford the title compound (0.8g, 74.5%) as a light yellow solid: LC-MS (ES) m/z=221 (M+H)⁺.

b) methyl 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate

A mixture of methyl 4-(1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate (300mg, 1.36 mmol) and NCS (218 mg, 1.63 mmol) in THF (5 mL) was heated to70° C. in a sealed tube. After 5 h, the reaction mixture wasconcentrated and purified via column chromatography (silica, 10-20%EtOAc/Hexane) affording the title compound (260 mg, 75%) as a whitesolid: LC-MS (ES) m/z 255 (M+H)⁺.

c)4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-furancarboxamide

To a solution of methyl4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate (250 mg, 0.98mmol) in THF/H₂O (5 mL/0.5 mL) was added KOH (200 mg, 3.56 mmol). Thereaction mixture was heated to 50° C. for 4 h. After the mixture wasconcentrated and diluted with H₂O (2 mL), the pH was adjusted to 3. Themixture was extracted with DCM (5 mL×3). The collected organic layerswere concentrated under vacuum to give a crude acid, which was useddirectly without further purification: LC-MS (ES) m/z 241 (M+H)⁺.

To the above crude acid in DCM (5 mL) at 25° C. was added PyBrOP (550mg, 1.18 mmol) in one portion, followed by the addition of DIPEA (0.7mL, 4.01 mmol). After 10 min,2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(322 mg, 1.08 mmol) was added to the reaction solution. After 2 h, thereaction mixture was concentrated and purified via column chromatography(silica, 20-50% EtOAc/Hexane) affording the title compound (360 mg, 70%)as a white solid: LC-MS (ES) m/z 521 (M+H)⁺.

d)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxamide

At RT, NH₂NH₂ (0.15 mL, 4.78 mmol) was added to a solution of4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-furancarboxamide(350 mg, 0.67 mmol) in MeOH (5 mL). After 10 h, the solvent was removedunder vacuum. The resulting residue was taken into DCM (15 mL) andwashed with H₂O (10 mL×3).

To the above DCM solution was added HCl (36%, 2 mL, 23.7 mmol)). After 1h, the aqueous phase was separated and washed with DCM (10 ml×3). Waterwas removed under high vacuum to give the title compound (260 mg, 78%)as an off-white solid: LC-MS (ES) m/z 391 (M+H)⁺. NMR (d₆-DMSO, 400 MHz)δ ppm 8.70 (m, 1H), 8.29 (s, 1H), 8.02 (m, 2H), 7.70 (s, 1H), 7.50-7.45(m, 1H), 7.36-7.30 (m, 1H), 7.14-7.08 (m, 2H), 7.06-7.01 (m, 1H), 4.43(m, 1H), 4.16 (q, J=7.3 Hz, 2H), 3.04-2.88 (m, 4H), and 1.30 (t, J=7.3Hz, 3H).

Example 254N-[2-amino-1-(phenylmethyl)ethyl]-3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl4-bromo-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate

To a solution of methyl4-bromo-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (0.948g, 4.0 mmol) in CH₂Cl₂ (5 mL) and pyridine (1 mL) at 0° C. was addedTf₂O (1.0 mL, 6.0 mmol). The mixture was stirred for 1 h, poured ontoice water (10 mL) and extracted with CH₂Cl₂ (5 mL×3). The collectedorganic layers were dried (Na₂SO₄) and concentrated to give a red syrupwhich was used directly in the next step without further purification:LC-MS (ES) m/z 370 (M+H)⁺.

b) methyl 4-bromo-3-methyl-2-thiophenecarboxylate

To a solution of methyl4-bromo-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (825mg, 2.25 mmol) in dioxane/H₂O (5 mL/1 mL) was added K₂CO₃ (930 mg, 6.75mmol), tetrakistriphenylphosphine Pd(0) (260 mg, 0.22 mmol), andmethylboronic acid (175 mg, 2.91 mmol). The reaction mixture was heatedto 70° C. in a sealed tube for 12 h. The reaction solution wasconcentrated under vacuum and purified on silica gel (hexanes/EtOAc,9:1) to give the title compound (441 mg, 84%) as a brown solid: LC-MS(ES) m/z 236 (M+H)⁺.

c) methyl 4-[1-(dimethylamino)ethenyl]-3-methyl-2-thiophenecarboxylate

To a solution of methyl 4-bromo-3-methyl-2-thiophenecarboxylate (300 mg,1.27 mmol) in dioxane/H₂O (5 mL/1 mL) was added K₂CO₃ (525 mg, 3.80mmol), tetrakistriphenylphosphine Pd(0) (15 mg, 0.01 mmol), and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(345 mg, 1.7 mmol). The reaction mixture was heated to 70° C. in asealed tube for 2 h. The reaction solution was concentrated under vacuumand purified on silica gel (hexanes/EtOAc, 9:1 to 4:1) to give the titlecompound (270 mg, 90%): LC-MS (ES) m/z 237 (M+H)⁺.

d)1,1-dimethylethyl[2-({[3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of methyl4-[1-(dimethylamino)ethenyl]-3-methyl-2-thiophenecarboxylate (50 mg,0.21 mmol) in THF/H₂O (2 mL/0.5 mL) was added KOH (122 mg, 2.1 mmol).The resulting mixture was heated to 50° C. for 2 h. The THF was removedunder vacuum and the aqueous layer was acidified with 6 N HCl to pH 3and extracted with CH₂Cl₂ (5 mL×3). The organic fractions was dried overNa₂SO₄ and concentrated to give the crude3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid, whichwas used directly in the next step.

To a solution of the crude3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid in DCM(2 mL) was added PyBrop (0.14 g, 0.3 mmol) and DIPEA (0.1 mL, 0.57mmol). After 15 min, 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamatewas added to the reaction in one portion and stirred for 2 h at RT. Thereaction solution was concentrated under vacuum and purified on silicagel (EtOAc/Hexane, 20-50%) to give the title compound (51 mg, 49% fortwo steps) as a solid: LC-MS (ES) m/z 455 (M+H)⁺.

e)N-[2-amino-1-(phenylmethyl)ethyl]-3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of1,1-dimethylethyl[2-({[3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(51 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction wasstirred over 5 h, concentrated and purified by reverse-phase HPLC (C18column: H₂O/CH₃CN, 40-10%) to afford the bis-TFA salt of the titlecompound. (16 mg, 41%): LC-MS (ES) m/z 355 (M+H)⁺. NMR (d₄-MeOD, 400MHz) δ ppm 7.64 (s, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.36-7.30 (m, 4H),7.28-7.21 (m, 1H), 6.30 (d, J=2.0 Hz, 1H), 4.58 (m, 1H), 3.69 (s, 3H),3.27-3.13 (m, 2H), 3.07-2.93 (m, 2H), and 2.13 (s, 3H).

Example 255N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

a) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-2-thiophenecarboxylate (1.0 g, 4.5 mmol)in dioxane/H₂O (5:1, 12 mL) was added K₂CO₃ (1.86 mg, 13.5 mmol),tetrakistriphenylphosphine Pd(0) (300 mg, 0.25 mmol), and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.23 g, 5.9 mmol). The reaction mixture was heated to 75° C. in asealed tube for 2 h. The reaction mixture was concentrated and purifiedon silica gel (EtOAc/Hex 10-40%) to give the title compound (701 mg,70%) as a white solid: LC-MS (ES) m/z 223 (M+H)⁺.

b) methyl 4-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (700 mg, 3.15 mmol)in THF (5 mL) was added NIS (922 mg, 4.09 mmol) in one portion. Thereaction mixture was stirred at 75° C. for 10 h, and then cooled to roomtemperature. The reaction mixture was concentrated and purified onsilica gel (EtOAc/Hex 10-20%) to give the title compound (470 mg, 43%)as an off white solid: LC-MS (ES) m/z 350 (M+H)⁺.

c) methyl4-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate

To a solution of methyl4-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (470 mg, 1.35mmol), copper (I) iodide (256 mg, 1.35 mmol) and potassium fluoride (78mg, 1.35 mmol) in anhydrous DMF/HMPA (2 ml/2 mL) was addedtriethyl(trifluoromethyl)silane (745 mg, 4.04 mmol). The mixture washeated to 70° C. under N₂ in a sealed tube. After 10 h, the reaction wasquenched with NH₄Cl (sat'd) (2 mL), extracted with ether (5 mL×5) andwashed with distilled water (5 mL×5). The combined organic phase wasdried over Mg₂SO₄ and purified on silica (EtOAc/Hex, 10-30%) to affordthe title compound (0.29 g, 74%) as a yellow syrup: LC-MS (ES) m/z 291(M+H)⁺.

d)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

To a solution of methyl4-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate(150 mg, 0.52 mmol) in THF/H₂O (2 mL/0.5 mL) was added KOH (116 mg, 2.0mmol). The reaction mixture was heated to 50° C. for 2 h. After themixture was concentrated and diluted with H₂O, the pH was adjusted to 3.The mixture was extracted with DCM (5 mL×3). The collected organiclayers were concentrated under vacuum to give the crude acid, which wasused directly in the next step without further purification: LC-MS (ES)m/z 277 (M+H)⁺.

To the above acid in DCM (5 mL) at 25° C. was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (279 mg,0.59 mmol) in one portion, followed by the addition of DIPEA (0.5 mL,2.87 mmol) and2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(174 mg, 0.5 mmol). After 2 h, the solution was concentrated andpurified via column chromatography (silica, 1-10% MeOH/CHCl₃) affordingthe title compound (0.21 g, 67% for 2 steps): LC-MS (ES) m/z 607 (M+H)⁺.

e)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide(210 mg, 0.35 mmol) was dissolved in MeOH (2 mL) and was treated withNH₂NH₂ (0.5 mL, 15.9 mmol). The reaction was stirred over 10 h,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,40-10%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissovled in water, and neutralized with ammonium hydroxide.The mixture was extracted with DCM, dried over Na₂SO₄, and concentratedto give a free base of the title compound. The free base compound wasdissolved in MeOH and treated with HCl (aq). After stirring overnight,the reaction was concentrated to give the title compound (95 mg, 57%) asa white solid. LC-MS: LC-MS (ES) m/z 477 (M+H)⁺. NMR (d₆-DMSO, 400 MHz):6 ppm 8.92 (d, J=9.1 Hz, 1H), 8.06 (m, 4H), 7.99 (s, 1H), 7.69 (d, J=7.6Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.53 (m, 1H), 7.43 (m, 1H), 4.49 (m,1H), 3.83 (s, 3H), and 3.14-2.99 (m, 4H).

Example 256N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a suspension of NaH (60% in mineral oil, 4.0 g, 100 mmol) in THF (200mL) was added 1H-pyrazole (6.8 g, 100 mmol) at 0° C. portionwise. Afterstirring at RT for 1 h, Prl (17.85 g, 105 mmol) was added dropwise at 0°C. The reaction mixture was stirred for 10 h and monitored by LC-MS:m/e=111 (M+H)⁺. After the reaction was complete, NaI was removed byfiltration. The resulting 1-propyl-1H-pyrazole containing THF solutionwas used directly in the next step.

To the above THF solution of 1-propyl-1H-pyrazole was added n-BuLi (2.5Min Hexane, 40 mL, 100 mmol) at −78° C. The reaction solution was stirredfor 2 hours at RT and then re-cooled to −78° C. [J. Heterocyclic Chem.41, 931 (2004)]. To the reaction solution was added2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.6 g, 100 mmol).After 30 min at −78° C., the reaction was quenched with saturated NH₄Clsolution and extracted with DCM. The organics were dried over Na₂SO₄ andconcentrated under vacuum to afford the title compound as a brown solidwhich was used directly without further purification: LC-MS (ES) m/z 154(M+H)⁺ for [RB(OH)2].

b) methyl 4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-2-thiophenecarboxylate (221 mg, 1.0mmol) in dioxane/H₂O (5:1, 6 mL) was added K₂CO₃ (414 mg, 3.0 mmol),tetrakistriphenylphosphine Pd(0) (60 mg, 0.05 mmol), and1-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(404 mg, 1.5 mmol). The reaction mixture was heated to 70° C. in asealed tube for 2 h. The reaction mixture was concentrated and purifiedon silica gel (EtOAc/Hex 10-40%) to give the title compound (176 mg,70%) as a white solid: LC-MS (ES) m/z 251 (M+H)⁺.

c)N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of methyl4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (160 mg, 0.64 mmol)in THF/H₂O (2 mL/1 mL) was added KOH (151 mg, 2.56 mmol). The reactionmixture was heated to 50° C. for 2 h. After the mixture was concentratedand diluted with H₂O, the pH was adjusted to 3. The mixture wasextracted with DCM (5 mL×3). The collected organic layers wereconcentrated under vacuum to give the crude acid, which was useddirectly in the next step without further purification. LCMS (ES)m/z=237 (M+H)⁺.

To the above acid in DCM (2 mL) at 25° C. was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (298 mg,0.64 mmol) in one portion, followed by the addition of DIPEA (0.2 mL,1.15 mmol) and2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(208 mg, 0.6 mmol). After 1 h, the solution was concentrated andpurified via column chromatography (silica, 1-10% MeOH/CHCl₃) affordingthe title compound (0.22 g, 61% for 2 steps): LC-MS (ES) m/z 567 (M+H)⁺.

d)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(220 mg, 0.36 mmol) was dissolved in MeOH (2 mL) and was treated withNH₂NH₂ (0.3 mL, 9.56 mmol). The reaction was stirred over 10 h,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,95-5%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissovled in water and neutralized with ammonium hydroxide. Themixture was extracted with DCM, dried over Na₂SO₄, and concentrated togive a free base of the title compound. The free base compound wasdissolved in MeOH (2 mL) and treated with HCl (4M in dioxane). Afterstirring overnight, the reaction solution was concentrated to give thetitle compound (112 mg, 57%) as an off white solid: LC-MS (ES) m/z 437(M+H)⁺, NMR (d₆-DMSO, 400 MHz): 6 ppm 9.06-8.99 (m, 1H), 8.23-8.02 (m,4H), 7.92 (br s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.62-7.49 (m, 3H), 7.42(m, 1H), 4.50 (m, 1H), 4.20 (m, 2H), 3.15-2.99 (m, 4H), 1.74 (m, 2H),and 0.80 (t, J=7.3 Hz, 3H).

Example 257N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-chloro-1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A mixture of methyl 4-(1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate(250 mg, 1.0 mmol) and NCS (200 mg, 1.5 mmol) in THF (5 mL) was heatedto 70° C. in a sealed tube. After 2 h, the reaction mixture wasconcentrated and purified via column chromatography (silica, 10%EtOAc/Hexane) affording the title compound (199 mg, 70%) as a whitesolid: LC-MS (ES) m/z 285 (M+H)⁺.

b)4-(4-chloro-1-propyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of methyl4-(4-chloro-1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (199 mg,0.7 mmol) in THF/H₂O (2 mL/0.5 mL) was added KOH (100 mg, 1.7 mmol). Thereaction mixture was heated to 50° C. for 2 h. After the mixture wasconcentrated and diluted with H₂O, the pH was adjusted to 3. The mixturewas extracted with DCM (5 mL×3). The collected organic layers wereconcentrated under vacuum to give the crude acid, which was useddirectly in the next step without further purification: LC-MS (ES) m/z271 (M+H)⁺.

To the above acid in DCM (5 mL) at 25° C. was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (326 mg,0.7 mmol) in one portion, followed by the addition of DIPEA (0.3 mL,1.15 mmol) and2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(232 mg, 0.7 mmol). After 10 min, the solution was concentrated andpurified via column chromatography (silica, 1-10% MeOH/CHCl₃) affordingthe title compound (312 mg, 74% for 2 steps): LC-MS (ES) m/z 601 (M+H)⁺.

c)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(4-Chloro-1-propyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide(312 mg, 0.52 mmol) was dissolved in MeOH (2 mL) and was treated withNH₂NH₂ (0.5 mL, 15.9 mmol). The reaction was stirred over 10 h,concentrated and purified by reverse-phase HPLC (C18 column: H₂O/CH₃CN,95-5%) to afford the bis-TFA salt of the title compound. The bis-TFAsalt was dissovled in water and neutralized with ammonium hydroxide. Themixture was extracted with DCM, dried over Na₂SO₄, and concentrated togive a free base of the title compound. The free base compound wasdissolved in MeOH (2 mL) and treated with HCl (aq). After stirringovernight, the reaction was concentrated to give the title compound (185mg, 66%) as an off white solid: LC-MS (ES) m/z 471 (M+H)⁺, NMR (d₄-MeOD,400 MHz) δ ppm 7.92 (m, 2H), 7.74-7.68 (m, 1H), 7.60 (s, 1H), 7.58-7.51(m, 2H), 7.45-7.41 (m, 1H), 4.67 (m, 1H), 4.15 (t, J=7.1 Hz, 2H),3.37-3.09 (m, 4H), 1.77 (m, 2H), and 0.82 (t, J=7.6 Hz, 3H).

Example 258N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 100 mL sealed flask was added1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.61 g, 11.74 mmol), potassium carbonate (3.25 g, 23.48 mmol), methyl4-bromo-5-chloro-2-thiophenecarboxylate (2 g, 7.83 mmol) andbis(tri-t-butylphosphine)palladium(0) (0.4 g, 0.78 mmol) in1,2-dimethoxyethane (DME) (50 mL) and H₂O (10 ml). After stirring for 3h at 70° C., the reaction solution was diluted with DCM (100 mL) andwashed with H₂O. The organic layer was dried Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel [EtOAc/hexanes,10-30%] to give the product [1.8 g, 85%] as an off white solid: LC-MS(ES) m/z 271 (M+H)⁺.

b) methyl5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.8g, 6.65 mmol) and NCS (1.3 g, 9.74 mmol) in THF (10 mL) were heated to70° C. under N₂ for 2 h. The reaction solution was concentrated andpurified on silica (EtOAc/Hex, 10-30%) to afford the title compound (1.5g, 74%) as a syrup: LC-MS (ES) m/z 305 (M+H)⁺.

b)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound (290 mg, 58.4%) was prepared as an off-white solidaccording to the procedure of Example 236, except substituting5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide(526 mg, 1.662 mmol) for5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide:LC-MS (ES) m/z 459 (M+H)⁺,

NMR (d₄-MeOD, 400 MHz) δ ppm 7.76 (m, 1H), 7.62 (s, 1H), 7.28-7.22 (m,1H), 7.20-7.10 (m, 2H), 4.52 (m, 1H), 4.07 (m, 2H), 3.27-3.16 (m 2H),3.05-2.94 (m, 2H), and 1.34 (m, 3H).

Example 259N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate

To a 100 mL sealed flask was added1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.61 g, 11.74 mmol), potassium carbonate (3.25 g, 23.48 mmol), methyl4-bromo-5-chloro-2-furancarboxylate (1.85 g, 8.33 mmol) andbis(tri-t-butylphosphine)palladium(0) (0.16 g, 0.31 mmol) in1,2-Dimethoxyethane (DME) (30 mL) and H₂O (5 mL). After stirring for 2 hat 75° C., the reaction solution was diluted with DCM (100 mL) andwashed with H₂O. The organic layer was dried Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel [EtOAc/hexanes,10-30%] to give the product (0.8 g, 50.1%) as an off-white solid: LC-MS(ES) m/z 255 (M+H)⁺.

b) methyl5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate

A mixture of methyl5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 3.14mmol) and NCS (600 mg, 4.49 mmol) in THF (5 mL) was heated to 70° C. ina sealed tube. After 2 h, the reaction mixture was concentrated andpurified via column chromatography (silica, 10-20% EtOAc/Hexane)affording the title compound (710 mg, 78%) as a white solid: LC-MS (ES)m/z 289 (M+H)⁺.

c)5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide

To a solution of methyl5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate (480mg, 1.66 mmol) in THF/H₂O (5 mL/1 mL) was added KOH (460 mg, 8.20 mmol).The reaction mixture was heated to 50° C. for 4 h. After the mixture wasconcentrated and diluted with H₂O (2 mL), the pH was adjusted to 3. Themixture was extracted with DCM (10 mL×3). The collected organic layerswere concentrated under vacuum to give a crude acid (420 mg, 92%), whichwas used directly without further purification: LC-MS (ES) m/z 275(M+H)⁺.

To the above acid (400 mg) in DCM (5 mL) at 25° C. was added PyBrOP (881mg, 1.89 mmol) in one portion, followed by the addition of DIPEA (1.5mL, 8.59 mmol). After 10 min,2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(506 mg, 1.60 mmol) was added. After 2 h, the reaction mixture wasconcentrated and purified via column chromatography (silica, 30-50%EtOAc/Hexane) affording the title compound (655 mg, 79%) as a whitesolid: LC-MS (ES) m/z 573 (M+H)⁺.

c)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-furancarboxamide

At RT, NH₂NH₂ (0.5 mL, 15.93 mmol) was added to a solution of5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide(610 mg, 1.06 mmol) in MeOH (5 mL). After 10 h, the solvent was removedunder vacuum. The resulting residue was taken into DCM (20 mL) andwashed with H₂O (20 mL×3).

To the DCM solution was added HCl (36%, 10 mL, 120 mmol). After 1 h, theaqueous phase was separated and washed with DCM (30 ml×3). Water wasremoved under high vacuum to give the title compound (410 mg, 87%) as anoff-white solid: LC-MS (ES) m/z 443 (M+H)⁺, NMR (d₄-MeOD, 400 MHz) δ ppm7.61 (s, 1H), 7.36 (s, 1H), 7.29-7.10 (m, 3H), 4.57 (m, 1H), 4.09 (q,J=7.3 Hz, 2H), 3.27-3.23 (m, 1H), 3.20-3.14 (m, 1H), 3.06-3.01 (m, 1H),2.97-2.92 (m, 1H), and 1.36 (t, J=7.3 Hz, 3H).

Example 260

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

A mixture of 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate(prepared according to Preparation 22 except substituting2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione for2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione)(236 mg, 0.537 mmol), 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole(200 mg, 0.537 mmol) (prepared according to patent IPN WO97/01553),Pd(PPh₃)₂Cl₂ (37.7 mg, 0.054 mmol), TRIETHYLAMINE (74.9 μl, 0.537 mmol)and toluene (3 ml) was degassed by N₂ and sealed. The reaction mixturewas heated at 110° C. for 4 hr. LC/MS showed the reaction was completed.The reaction mixture was concentrated and purified via columnchromatography (silica, 70% EtOAc in hexane) to give the title product(120 mg, 51%) LCMS (ES) m/z=442.2 (M+H)

b)N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(60 mg, 0.14 mmol) in TFA-DCM (4 ml, 1:3) was stirred at rt for 1 h.LCMS showed the reaction was completed. The reaction mixture wasconcentrated and the residue was purified by reverse phase HPLC (5%-65%acetonitrile in water with 0.1% TFA) to give 42.2 mg (67%) of the TFAsalt as a white solid. LCMS (ES) m/z 342.2 (M+H)⁺, ¹H NMR (400 MHz,METHANOL-d4)

ppm 8.06 (d, J=1.52 Hz, 1H), 7.87-7.91 (m, 2H), 7.34-7.21 (m, 5H), 4.55(m, 1H), 4.19 (s, 3H), 3.30-3.21 (m, 1H), 3.09-3.18 (m, 1H), 3.01 (d,J=7.6 Hz, 2H)

Example 261

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamidea)1,1-Dimethylethyl[(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(70 mg, 0.16 mmol) in 2 ml of DMF was added NCS (42.3 mg, 0.32 mmol).The reaction mixture was heated at 50° C. for 2 hr and then diluted with50 ml of EtOAc. The organic layer was washed with H₂O and concentratedto give the title product as a crude mixture, which was used in nextstep without purification. LCMS (ES) m/z=510.2 (M+H)

b)N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(crude from a) in TFA-DCM (4 ml, 1:3) was stirred at rt for 1 h. Thereaction mixture was concentrated and the residue was purified byreverse phase HPLC (5%-65% acetonitrile in water with 0.1% TFA) to give10 mg (12% two steps) of white solid as TFA salt. LCMS (ES) m/z410.0/412.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.62 (s, 1H), 7.32-7.25 (m, 5H), 4.55 (m, 1H), 4.02 (s, 3H), 3.21(m, 1H), 3.10 (m, 1H), 2.98 (d, 2H).

Example 262

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 260, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(4-fluorophenyl)propyl]carbamate(123 mg, 0.27 mmol) for 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.LCMS (ES) m/z 360.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.05 (d, J=1.6 Hz, 1H), 7.89-7.91 (m, 2H), 7.33-7.30 (m, 2H,7.06-7.02 (m, 2H), 4.55 (m, 1H), 4.20 (s, 3H), 3.23 (m, 1H), 3.17 (m,1H), 2.99 (m, 2H).

Example 263

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamidea)1,1-Dimethylethyl[(2S)-3-(3,4-difluorophenyl)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)propyl]carbamate

A solution of1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-di-fluorophenyl)propyl]carbamate(50 mg, 0.11 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole(44 mg, 0.21 mmol), Na₂CO₃ (2N, 0.1 ml) and PddppfCl₂ (8.6 mg, 0.01mmol) in 3 ml of 1,4-dioxane was irradiated in MW reactor at 150° C. for20 min. The crude reaction mixture was purified by column chromatography(silica, 70% EtOAc in hexane) to give the title product (29 mg, 46%):LCMS (ES) m/z=478.2 (M+H).

b)N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared according to Example 260b) exceptsubstituting1,1-dimethylethyl[(2S)-3-(3,4-difluorophenyl)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)propyl]carbamate(29 mg, 0.06 mmol) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 378.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.07 (d, J=1.6 Hz, 1H), 7.88-7.91 (m, 2H), 7.23-7.09 (m, 3H), 4.55(m, 1H), 4.20 (s, 3H), 3.24 (m, 1H), 3.15 (m, 1H), 2.98 (m, 2H).

Example 264

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substituting1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-(4-fluorophenyl)propyl]carbamate(68 mg, 0.15 mmol) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 428.0/430.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.66 (s, 1H), 7.30 (m, 2H), 7.04 (m, 2H), 4.55 (m, 1H), 4.02 (s, 3H,3.21-3.10 (m, 2H), 2.98 (m, 2H).

Example 265

PreparationN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 263, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3-fluorophenyl)propyl]carbamate(300 mg, 0.66 mmol) for1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.LCMS (ES) m/z 360.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.06 (d, J=1.6 Hz, 1H), 7.90 (m, 2H), 7.33-7.30 (m, 1H), 7.13-7.09(m, 2H), 6.98-6.95 (m, 1H), 4.55 (m, 1H), 4.19 (s, 3H), 3.24 (m, 1H),3.17 (m, 1H), 3.04-2.99 (m, 2H).

Example 266

PreparationN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 263, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,5-difluorophenyl)propyl]carbamate(300 mg, 0.66 mmol) for1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.LCMS (ES) m/z 378.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.06 (d, J=1.6 Hz, 1H), 7.91 (m, 2H), 6.96-6.93 (m, 2H), 6.84-6.83(m, 1H), 4.55 (m, 1H), 4.19 (s, 3H), 3.24 (m, 1H), 3.19 (m, 1H),3.05-2.98 (m, 2H).

Example 267

PreparationN-{(1S)-2-amino-1-[(3-trifluoromethylphenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 263, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3-(trifluoromethyl)phenyl)propyl]carbamate(500 mg, 0.99 mmol) for1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.LCMS (ES) m/z 410.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.06 (d, J=1.2 Hz, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.72 (d, J=1.2Hz, 1H) 7.54 (m, 2H), 7.44 (m, 1H), 4.55 (m, 1H), 4.21 (s, 3H),3.30-3.10 (m, 4H).

Example 268

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substituting1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-(3-fluorophenyl)propyl]carbamate(50 mg, 0.11 mmol) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 428.0/430.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.63 (s, 1H), 7.33 (m, 1H), 7.12-7.07 (m, 3H), 4.55 (m, 1H), 4.02(s, 3H), 3.23-2.98 (m, 4H).

Example 269

Preparation ofN-{(1S)-2-amino-1-[(2-(trifluoromethyl)phenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamidea) methyl5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate

A mixture of 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole (2.0 g,5.37 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (1.25 g, 4.9mmol), Pd(PPh₃)₂Cl₂ (171 mg, 0.244 mmol), TRIETHYLAMINE (0.68 ml, 4.89mmol) and toluene (3 ml) was heated at 110° C. for 4 hr under N₂. Thereaction mixture was purified via column chromatography (silica, 50%-70%EtOAc in hexane) to give the title compound as a white solid (400 mg,32%): LCMS (ES) m/z 258.2 (M+H)⁺.

b) 5-Chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylicAcid

A solution of methyl5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate (400mg, 1.55 mmol) and 1N LiOH (2.0 ml, 2.0 mmol) in THF (6 ml) was stirredat rt overnight. After removal of THF, the residue was diluted with 10ml of H₂O and washed with DCM (10 ml×2). The aqueous layer was acidifiedto pH 3 with 1N HCl and then extracted with EtOAc (30 ml×4). The organiclayers were combined and concentrated to give 370 mg of the titlecompound as a white solid. LCMS (ES) m/z 244.0 (M+H)⁺

c)5-Chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

A solution of5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylic acid(370 mg, 1.52 mmol),2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione(from Preparation 6, 529 mg, 1.52 mmol), PyBrop (708 mg, 1.52 mmol) andDIPEA (2.65 ml, 15.2 mmol) in 20 ml of DCM was stirred at rt for 2 hr.The reaction mixture was diluted with 50 ml of DCM and washed with H₂O,0.1N HCl and brine. The organic layer was concentrated and the residuewas purified via column chromatography (silica, 50%-70% EtOAc in hexane)to give the title compound as a white solid (700 mg, 80%): LCMS (ES) m/z574.0 (M+H)⁺.

d)N-{(1S)-2-amino-1-[(2-(trifluoromethyl)phenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

A solution of5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide(700 mg, 1.22 mmol) and hydrazine (0.19 mL, 6.1 mmol) in 5 mL of MeOHwas stirred at rt overnight, diluted with 200 ml of H₂O and extractedwith DCM (100 ml×2). The combined organic layers were concentrated andthe resulting solid was dissolved in 6N HCl (50 ml). The aqueous layerwas washed with DCM (50 ml×2). The organic layers were discarded and theremaining aqueous solution was concentrated to give the product as anHCl salt (490 mg, 75%): LCMS (ES) m/z 444.0 (M+H)⁺, ¹H NMR (400 MHz,METHANOL-d4)

ppm 8.10 (m, 1H), 7.92 (m, 1H), 7.73 (m, 1H), 7.57 (m, 1H), 7.44 (m,1H), 4.65 (m, 1H), 4.17 (s, 3H), 3.25-3.11 (m, 4H).

Example 270

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 269, except substituting methyl4-bromo-5-methyl-2-thiophenecarboxylate (from Preparation 10) for methyl4-bromo-5-chloro-2-thiophenecarboxylate and2-{(2S)-2-amino-3-phenylpropyl}-1H-isoindole-1,3(2H)-dione (preparation5) for2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 356.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.60 (s, 1H), 8.01 (s, 1H), 7.34-7.21 (m, 5H), 4.55 (m, 1H), 4.26(s, 3H), 3.25 (m, 2H), 3.03 (m, 2H), 2.21 (s, 3H).

Example 271

Preparation ofN-{(1S)-2-amino-1-[(2-(trifluoromethyl)phenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substitutingN-{(1S)-2-amino-1-[(2-(trifluoromethyl)phenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide(120 mg, 0.27 mmol) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 478.0/480.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.79 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.56 (m, 2H), 7.45 (m, 1H),4.65 (m, 1H), 4.05 (s, 3H), 3.29-3.10 (m, 4H).

Example 272

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substituting1,1-dimethylethyl[(2S)-2-({[5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(prepared in Example 270) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 390.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.72 (s, 1H), 7.31-7.22 (m, 5H), 4.55 (m, 1H), 3.99 (s, 3H), 3.19(m, 2H), 3.02 (m, 2H), 2.41 (s, 3H).

Example 273

Preparation ofN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamidea) Methyl 4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate

The title compound was prepared according to the procedure of Example269 a), except substituting methyl 4-bromo-2-thiophenecarboxylate formethyl 4-bromo-5-chloro-2-thiophenecarboxylate. LCMS (ES) m/z 224.0(M+H)⁺.

b) methyl4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate

A solution of methyl4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate (500 mg, 2.24mmol) and NCS (1196 mg, 8.96 mmol) in N,N-Dimethylformamide (DMF) (10ml) was heated at 50° C. for 2 hr. The reaction mixture was diluted with50 ml of EtOAc. The organic layer was washed with H₂O (50 ml×2) andbrine (50 ml), and then concentrated to give 460 mg of a crude mixture,which was used in next step without further separation. LCMS (ES) m/z258.0 (M+H)⁺.

c) 4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylicAcid

The title compound was prepared following the procedure of Example 269b), except substituting methyl4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate formethyl4-(1-methyl-1H-1,2,3-triazol-5-yl)-5-chloro-2-thiophenecarboxylate. LCMS(ES) m/z 244.0 (M+H)⁺.

d)N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared following the procedure of Example269c-d), except substituting4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylic acidfor 4-(1-methyl-1H-1,2,3-triazol-5-yl)-5-chloro-2-thiophenecarboxylicacid and substituting2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dionefor2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 412.0/414.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.13 (m, 1H), 8.06 (m, 1H), 6.97 (m, 2H), 6.82 (m, 1H), 4.55 (m,1H), 4.16 (s, 3H), 3.26 (m 2H), 3.04 (m, 2H).

Example 274

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared following the procedure of Example 273,except substituting2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(82 mg, 0.15 mmol) for2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 412.0/414.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.12 (d, J=1 Hz, 1H), 8.05 (d, J=1 Hz, 1H) 7.30-7.10 (m, 3H), 4.55(m, 1H), 4.16 (s, 3H), 3.26 (m 2H), 2.99 (m, 2H).

Example 275

Preparation ofN-{(1S)-2-amino-1-[(2-(trifluoromethyl)phenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared following the procedure of Example 274,except substituting2-[(2S)-2-amino-3-(2-(trifluoromethyl)phenyl)propyl]-1H-isoindole-1,3(2H)-dione(130 mg, 0.23 mmol) for2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 444.0/446.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.13 (d, J=1 Hz, 1H), 8.09 (d, J=1 Hz, 1H), 7.72 (m, 1H), 7.56 (m,2H), 7.43 (m, 1H), 4.60 (m, 1H), 4.17 (s, 3H), 3.26-3.15 (m, 4H).

Example 276

Preparation ofN-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared following the procedure of Example 273,except substituting2-[(2S)-2-amino-3-(4-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (73mg, 0.14 mmol) for2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 410.0/412.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.12 (d, J=1 Hz, 1H), 8.03 (d, J=1 Hz, 1H), 7.31 (m, 4H), 4.55 (m,1H), 4.15 (s, 3H), 3.26 (m 2H), 3.05 (m, 2H).

Example 277

Preparation ofN-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared following the procedure of Example 273,except substituting2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(67 mg, 0.12 mmol) for2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 444.0/448.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.12 (d, J=1 Hz, 1H), 8.03 (d, J=1 Hz, 1H), 7.49 (d, 1H), 7.38 (d,1H), 7.25 (m, 1H), 4.60 (m, 1H), 4.16 (s, 3H), 3.30-3.09 (m, 4H).

Example 278

PreparationN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 263, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(cyclohexyl)propyl]carbamate(300 mg, 0.67 mmol) for1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.LCMS (ES) m/z 348.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.09 (d, J=1 Hz, 1H), 8.03 (d, J=1 Hz, 1H), 7.91 (s, 1H), 4.48 (m,1H), 4.22 (s, 3H), 3.20 (m 1H), 3.05 (m, 1H), 2.00-0.95 (m, 13H).

Example 279

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substituting1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-cyclolhexylpropyl]carbamate(50 mg, 0.11 mmol) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 416.0/418.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.74 (s, 1H), 4.48 (m, 1H), 4.04 (s, 3H), 3.40-2.95 (m 2H),1.90-0.95 (m, 13H).

Example 280

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 269, except substituting2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione for2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 382.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.93 (s, 1H), 7.81 (m, 1H), 4.43 (m, 1H), 4.10 (s, 3H), 3.17 (m 1H),3.05 (m, 1H), 2.00-0.90 (m, 13H).

Example 281

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off white solid according to theprocedure of 261, except substituting1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-cyclolhexylpropyl]carbamate(100 mg, 0.22 mmol) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate,and the amount of NCS was reduced to 1 eq. LCMS (ES) m/z 382.2 (M+H)⁺,¹H NMR (400 MHz, METHANOL-d4)

ppm 8.15 (d, J=1 Hz, 1H), 8.08 (d, J=1 Hz, 1H), 4.45 (m, 1H), 4.16 (s,3H), 3.14 (m 1H), 3.05 (m, 1H), 2.00-0.90 (m, 13H).

Example 282

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[(2S)-2-({[5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-cyclohexylpropyl]carbamate(140 mg, 0.29 mmol, prepared in Example 280) and NBS (103 mg, 0.58 mmol)in 2 mL of DMF was heated at 100° C. for 2 hours. The reaction mixturewas purified by reverse phase HPLC (5-65% acetonitrile in H₂O with 1%TFA) to give the title compound 14.1 mg (8%) as a white solid. LCMS (ES)m/z 462.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.75 (s, 1H), 4.43 (m, 1H), 4.05 (s, 3H), 3.17 (m 1H), 3.05 (m, 1H),2.00-0.90 (m, 13H).

Example 283

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 260, except substituting1,1-dimethylethyl[(2S)-2-{[(5-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl]carbamate(270 mg, 0.62 mmol) for 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.LCMS (ES) m/z 342.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.96 (s, 1H), 7.75 (d, J=3.6 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H),7.31-7.22 (m, 5H), 4.55 (m, 1H), 4.21 (s, 3H), 3.20 (m, 2H) 2.99 (m,2H).

Example 284

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substituting1,1-dimethylethyl[(2S)-2-({[5-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(68 mg, 0.15 mmol) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 376.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.82 (m, 1H), 7.55 (d, J=3.6 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H),7.32-7.23 (m, 5H), 4.55 (m, 1H), 4.19 (s, 3H), 3.20 (m, 2H), 3.02 (m,2H).

Example 285

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 269, except substituting methyl4-bromo-5-methyl-2-furancarboxylate (ref. Bach, T.; Kruger, L. Synlett1998, 1185-1186) for methyl 4-bromo-5-chloro-2-thiophenecarboxylate.LCMS (ES) m/z 408.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.09 (s, 1H), 7.71 (m, 1H), 7.55 (m, 2H), 7.43 (m, 2H), 4.68 (m,1H), 4.13 (s, 3H), 3.25-3.15 (m, 4H), 2.48 (s, 3H).

Example 286

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 260, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-furanyl)carbonyl]amino}-3-(2-(trifluoromethyl)phenyl)propyl]carbamate(200 mg, 0.4 mmol) for 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.LCMS (ES) m/z 394.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.23 (s, 1H), 7.93 (s, 1H), 7.71 (d, 1H), 7.54 (m, 2H), 7.43 (m,2H), 4.75 (m, 1H), 4.18 (s, 3H), 3.30-3.10 (m, 4H).

Example 287

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substituting1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furanyl]carbonyl}amino)-3-(2-(trifluoromethyl)phenyl)propyl]carbamate(90 mg, 0.18 mmol) for 1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate.LCMS (ES) m/z 462.0/464.0 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.73 (m, 1H), 7.56 (m, 2H), 7.45 (m, 1H), 7.40 (s, 1H), 4.75 (m,1H), 4.05 (s, 3H), 3.30-3.10 (m, 4H).

Example 288

Preparation ofN-((1S)-2-amino-1-{[3-fluorophenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 269, except substituting methyl4-bromo-5-methyl-2-furancarboxylate for methyl4-bromo-5-chloro-2-thiophenecarboxylate and2-{(2S)-2-amino-3-[3-fluorophenyl]propyl}-1H-isoindole-1,3(2H)-dione for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 358.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.47 (s, 1H), 7.44 (s, 1H), 7.35 (m, 1H), 7.15 (m, 2H), 6.96 (m,1H), 4.65 (m, 1H), 4.22 (s, 3H), 3.25 (m, 2H), 3.04 (m, 2H), 2.49 (s,3H).

Example 289

Preparation ofN-((1S)-2-amino-1-{[3,5-difluorophenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide

The title compound was prepared as an off-white solid according to theprocedure of Example 269, except substituting methyl4-bromo-5-methyl-2-furanocarboxylate for methyl4-bromo-5-chloro-2-thiophenecarboxylate and2-{(2S)-2-amino-3-[3,5-difluorophenyl]propyl}-1H-isoindole-1,3(2H)-dionefor2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione.LCMS (ES) m/z 376.2 (M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 8.30 (s, 1H), 7.43 (s, 1H), 6.95 (m, 2H), 6.82 (m, 1H), 4.53 (m,1H), 4.18 (s, 3H), 3.25 (m, 2H), 3.07 (m, 2H), 2.48 (s, 3H).

Example 290

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 261, except substitutingN-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide(prepared according to Example 263) for1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamateand following Example 269 for deprotection. LCMS (ES) m/z 446.0/448.0(M+H)⁺, ¹H NMR (400 MHz, METHANOL-d4)

ppm 7.88 (s, 1H), 7.20-7.15 (m, 3H), 4.53 (m, 1H), 4.05 (s, 3H), 3.23(m, 2H), 3.00 (m, 2H).

Example 291

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

A suspension of 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate(prepared according to preparation 22 except substituting2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione for2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione)(200 mg, 0.455 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane(123 mg, 0.546 mmol), potassium acetate (134 mg, 1.366 mmol), andPdCl₂(dppf)₂ (16.7 mg, 0.023 mmol) in dry THF (3 ml) was charged into asealed tube and heated to 80° C. for one hour.5-Iodo-1-methyl-1H-1,2,4-triazole (114 mg, 0.546 mmol), 2M sodiumcarbonate (0.34 ml, 0.683 mmol) and Pd(Ph₃P)₄ (26.3 mg, 0.023 mmol) werethen added. The mixture was heated at 85° C. for 2 hours. The solventwas removed and the residue was purified by biotage (70% H/E) to givethe title product (120 mg, 60%)

b)N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

TFA (1 ml) was added to a solution of1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate(100 mg, 0.226 mmol) in DCM (5 ml). The reaction was stirred at RT for30 min. The solvent was removed and the residue was purified by reversephase HPLC (10% org˜60% org) to give the title compound as a white solid(90 mg, 87%). LC-MS (ES) m/z 342.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ8.23 (s, 1H), 8.03 (m, 2H), 7.22-7.31 (m, 5H), 4.60 (m, 1H), 4.08 (s,3H), 3.10-3.20 (m, 2H), 3.00 (m, 2H).

Example 292

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[(2S)-3-(3,4-difluorophenyl)-2-({[4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)propyl]carbamate

This intermediate was prepared according to the procedure of Example 291a) except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.LC-MS (ES) m/z=478.2 (M+H)⁺

b)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

A solution of1,1-dimethylethyl[(2S)-3-(3,4-difluorophenyl)-2-({[4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)propyl]carbamate(279 mg, 0.497 mmol) and NCS (133 mg, 0.993 mmol) inN,N-Dimethylformamide (DMF) (3 ml) was heated at 110° C. for 1 hr. Thecrude reaction mixture was concentrated and the residue was purified byflash column chromatography on silica gel (DCM:MeOH:NH₄OH 9:1:1) to givethe product as a free base, which was treated with 0.13 mL of 2N HCl aq.(2 eq.) to give 75 mg of HCl salt as an off-white solid. LC-MS (ES)m/z=412 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ 8.80 (s, 1H), 8.18 (s, 1H),7.3-7.1 (m, 3H), 4.54 (m, 1H), 4.11 (s, 3H), 3.26 (d, J=7 Hz, 2H), 3.03(d, J=8 Hz, 2H).

Example 293

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared an off-white solid according to theprocedure of Example 291 except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final product was purified by flash column chromatography on silicagel (DCM:MeOH:NH₄OH 9:1:1) to give a free base, which was treated with2N HCl aq. solution to give the HCl salt. LC-MS (ES) m/z=378 (M+H)⁺, ¹HNMR (CD₃OD, 400 MHz) δ 8.78 (s, 1H), 8.50 (d, J=2 Hz, 1H), 8.36 (d, J=2Hz, 1H), 7.3-7.1 (m, 3H), 4.57 (m, 1H), 4.23 (s, 3H), 3.27 (d, J=8 Hz,2H), 3.04 (d, J=8 Hz, 2H).

Example 294

Preparation ofN-[(1S,2S)-2-amino-3-hydroxy-1-phenylpropyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamidea)1,1-dimethylethyl[(1S,2S)-2-amino-1-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-phenylethyl]carbamate

The title compound was prepared according to Preparation 1 exceptsubstituting1,1-dimethylethyl[(1R,2R)-1-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-hydroxy-2-phenylethyl]carbamate(ref. Veeresa, G.; Datta, Apurba. Stereoselective synthesis ofchloramphenicol from D-serine. Tetrahedron Letters (1998), 39(46),8503-8504.) for 1,1-dimethylethyl (2-hydroxy-2-phenylethyl)carbamate.

b)N-[(1S,2S)-2-amino-3-hydroxy-1-phenylpropyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

This intermediate was prepared according to the procedures of Example261, except substituting1,1-dimethylethyl[(1S,2S)-2-amino-1-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-phenylethyl]carbamatefor 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate. LC-MS (ES)m/z=425.0/427.0 (M+H)⁺, ¹H NMR (CD₃OD, 400 MHz) δ 7.86 (s, 1H), 7.59 (s,1H), 7.56-7.38 (m, 5H), 5.50 (m, 1H), 3.91-3.84 (m, 3H).

Example 295

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]-ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamidea) Methyl 4-bromo-5-chloro-2-furancarboxylate

Isopropylmagnesium chloride (1.20 ml, 2.40 mmol) was added dropwise to asolution of methyl 4,5-dibromo-2-furancarboxylate (568 mg, 2.0 mmol) inTetrahydrofuran (THF) (16 ml) at 0° C. The resulting mixture was stirredat this temperature for 30 min and then cooled to −78° C. A solution ofhexylchloroethane (568 mg, 2.401 mmol) in THF (1 mL) was added dropwise,and the resulting mixture was stirred at this temperature for 1 hr. Thereaction was quenched with addition of NH₄Cl (sat. aq) and the resultingmixture was stirred at rt overnight. Ether and water were added and theaqueous layer was discarded. The organic layer was washed with brine,dried (Na₂SO₄) and concentrated to give 0.34 g of the product containingits isopropyl ester.

b)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-furancarboxamide

The title compound was prepared according to the procedure of Example273, except substituting methyl 4-bromo-5-chloro-2-furancarboxylate formethyl 4-bromo-2-thiophenecarboxylate, and substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione.The final product was purified by RP-HPLC and converted to HCl salt with2N HCl aqueous solution. LC-MS (ES) m/z=412.0/414.0 (M+H)⁺, ¹H NMR(CD₃OD, 400 MHz) δ 7.44 (s, 1H), 7.33 (m, 1H), 7.14-7.07 (m, 2H), 6.98(m, 1H), 4.55 (m, 1H), 4.05 (s, 3H), 3.25-2.98 (m, 4H).

Example 296

Preparation ofN-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl((2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate

A solution of 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate(prepared according to Preparation 22), except substituting2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione for2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(200 mg, 0.455 mmol) and NCS (61 mg, 0.455 mmol) in DMF (3 ml) washeated at 50° C. in a sealed tube for 2 hours. The solvent was removedand the residue was purified by biotage (30% Hex/EtOAc) to give thetitle product (140 mg, 65%).

b)N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according the procedureof Example 291, except substituting 1,1-dimethylethyl((2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.LC-MS (ES) m/z 376.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.12 (s, 1H),7.74 (s, 1H), 7.31-7.35 (m, 5H), 4.58 (m, 1H), 3.94 (s, 3H), 3.35 (m,2H), 3.05 (m, 2H).

Example 297

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 291, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}-carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate;LC-MS (ES) m/z 410.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.33 (m, 2H),7.73 (m, 1H), 7.41-7.56 (m, 4H), 4.70 (m, 1H), 4.13 (s, 3H), 3.36 (m,2H), 3.18 (m, 2H).

Example 298

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 291, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(4-fluorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.LC-MS (ES) m/z 360.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.24 (s, 1H),8.06 (m, 2H), 7.29-7.34 (m, 2H), 7.01-7.05 (m, 2H), 4.66 (m, 1H), 4.08(s, 3H), 3.23 (m, 2H), 3.15 (m, 2H).

Example 299

Preparation ofN-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 292, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(4-fluorophenyl)propyl]carbamatefor 1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.The final compound was purified by RP-HPLC to give the title compound asa white solid. LC-MS (ES) m/z 394.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ8.10 (s, 1H), 7.70 (s, 1H), 7.28-7.31 (m, 2H), 7.01-7.06 (m, 2H), 4.56(m, 1H), 3.92 (s, 3H), 3.21 (m, 2H), 2.96 (m, 2H).

Example 300

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 291, except substituting 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-cyclohexylpropyl)carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.LC-MS (ES) m/z 348.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.27 (m, 1H),8.13 (s, 1H), 8.02 (s, 1H), 4.56 (m, 1H), 4.11 (s, 3H), 3.16 (m, 1H),3.02 (m, 1H), 1.17-1.95 (m, 13H)

Example 301

Preparation ofN-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 292, except substituting 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-cyclohexylpropyl)carbamatefor1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.The final compound was purified by RP-HPLC to give the title compound asa white solid. LC-MS (ES) m/z 382.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ8.10 (s, 1H), 7.82 (s, br, 1H), 4.42 (m, 1H), 3.94 (s, 3H), 3.16-3.30(m, 1H), 2.98-3.10 (m, 1H), 1.06-1.96 (m, 13H)

Example 302

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 292, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamatefor1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate;The final compound was purified by RP-HPLC to give the title compound asa white solid. LC-MS (ES) m/z 444.0 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ8.20 (s, br, 1H), 7.86 (s, br, 1H), 7.71 (m, 1H), 7.42-7.56 (m, 3H),4.63 (m, 1H), 3.96 (s, 3H), 3.09-3.27 (m, 4H).

Example 303

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 291, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3-fluorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate;LC-MS (ES) m/z 360.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.24 (s, 1H),8.02 (m, 2H), 7.30 (m, 1H) 7.06-7.13 (m, 2H), 6.96 (m, 1H), 4.63 (m,1H), 4.08 (s, 3H), 3.09-3.27 (m, 4H).

Example 304

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 292, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3-fluorophenyl)propyl]carbamatefor 1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate;The final compound was purified by RP-HPLC to give the title compound asa white solid. LC-MS (ES) m/z 394.0 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ8.10 (s, 1H), 7.70 (s, 1H), 7.31 (m, 1H), 6.97-7.11 (m, 3H), 4.52 (m,1H), 3.92 (s, 3H), 2.96-3.26 (m, 4H)

Example 305

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example291, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propyl}carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate;The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 410.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.81 (s, 1H), 8.51 (d, J=1 Hz, 1H), 8.39 (d, J=1Hz, 1H), 7.64 (m, 2H), 7.50 (m, 2H), 4.66 (m, 1H), 4.23 (s, 3H), 3.30(m, 2H), 3.15 (m, 2H).

Example 306

Preparation ofN-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example292, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propyl}carbamatefor 1,1-dimethyl ethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 440.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.53 (s, 1H), 8.02 (s, 1H), 7.50-7.64 (m, 4H), 4.56(m, 1H), 4.03 (s, 3H), 3.10-3.27 (m, 4H).

Example 307

Preparation ofN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example291, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,5-difluorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate;The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 378.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.68 (s, 1H), 8.47 (d, J=1 Hz, 1H), 8.35 (d, J=1Hz, 1H), 6.96 (m, 2H), 6.80 (m, 1H), 4.60 (m, 1H), 4.21 (s, 3H), 3.28(m, 2H), 3.08 (m, 2H).

Example 308

Preparation ofN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example292, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,5-difluorophenyl)propyl]carbamatefor 1,1-dimethyl ethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate;The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 412.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.44 (s, 1H), 7.98 (s, 1H), 6.96 (m, 2H), 6.82 (m,1H), 4.66 (m, 1H), 4.01 (s, 3H), 3.20-3.25 (m, 2H), 3.02-3.05 (m, 2H).

Example 309

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamidea) 1,1-dimethylethyl{(2S)-2-{[(4-bromo-5-methyl-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

This intermediate was prepared according to Preparation 22, exceptsubstituting 4-bromo-5-methyl-2-thiophenecarboxylic acid (Bioorganic &Medicinal Chemistry Letters (2002), 12(3), 491-495) for4-bromo-2-thiophenecarboxylic acid, and substituting2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dionefor2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.

b)N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 291, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-5-methyl-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate:The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 424.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.68 (s, 1H), 8.04 (s, 1H), 7.70 (m, 1H), 7.58 (m,1H), 7.52 (m, 1H), 7.43 (m, 1H), 4.65 (m, 1H), 4.05 (s, 3H), 3.16-3.28(m, 4H), 2.59 (s, 3H)

Example 310

Preparation ofN-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 291, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(2-fluorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate;LC-MS (ES) m/z 360.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.60 (s, 1H),8.43 (d, J=1 Hz, 1H), 8.24 (d, J=1 Hz, 1H), 7.37 (m, 1H), 7.27 (m, 1H),7.08 (m, 2H), 4.66 (m, 1H), 4.19 (s, 3H), 3.27 (m, 2H), 3.10 (s, 2H)

Example 311

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 260, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-5-methyl-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 360.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.31 (s, 1H), 7.94 (s, 1H), 7.70 (m, 1H), 7.56 (m,2H), 7.43 (m, 1H), 4.65 (m, 1H), 4.19 (s, 3H), 3.15-3.28 (m, 4H), 2.50(s, 3H).

Example 312

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example261, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-5-methyl-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 458.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 7.70 (m, 2H), 7.55 (m, 2H), 7.44 (m, 1H), 4.67 (m,1H), 3.99 (s, 3H), 3.12-3.21 (m, 4H), 2.42 (s, 3H).

Example 313

Preparation ofN-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 292, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(4-fluorophenyl)propyl]carbamatefor 1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 394.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.49 (s, 1H), 7.95 (s, 1H), 7.27-7.36 (m, 2H),7.06-7.13 (m, 2H), 4.61 (m, 1H), 4.03 (s, 3H), 3.02-3.25 (m, 4H).

Example 314

Preparation ofN-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to Example291, except substituting 1,1-dimethylethyl{(2S)-2-{[(4-bromo-2-furanyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 394.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.50 (s, 1H), 8.43 (s, 1H), 7.71 (m, 1H), 7.61 (s,1H), 7.54 (m, 2H), 7.42 (m, 1H), 4.66 (m, 1H), 4.14 (s, 3H), 3.25 (m,2H), 3.14 (m, 2H).

Example 315

Preparation ofN-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example260, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(2,4-dichlorophenyl)propyl]carbamate(from Preparation 22) for 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 410.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.23 (s, 1H), 8.14 (m, 2H), 7.47 (d, J=1 Hz, 1H),7.41 (d, J=1 Hz, 1H), 7.25 (m, 1H), 4.68 (m, 1H), 4.30 (s, 3H),3.11-3.28 (m, 4H).

Example 316

Preparation ofN-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example291, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(2,4-dichlorophenyl)propyl]carbamate(from Preparation 22) for 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 410.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.71 (s, 1H), 8.47 (d, J=1 Hz, 1H), 8.34 (d, J=1Hz, 1H), 7.45 (m, 2H), 7.23 (m, 1H), 4.71 (m, 1H), 4.23 (s, 3H),3.14-3.22 (m, 4H)

Example 317

Preparation ofN-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 292, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(2,4-dichlorophenyl)propyl]carbamatefor 1,1-dimethyl ethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 446.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.65 (s, 1H), 8.11 (s, 1H), 7.44 (m, 2H), 7.25 (m,1H), 4.68 (m, 1H), 4.08 (s, 3H), 3.10-3.23 (m, 4H).

Example 318

Preparation ofN-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example261, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(2,4-dichlorophenyl)propyl]carbamate(from Preparation 21) for 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 480.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 7.80 (m, 1H), 7.48 (m, 1H), 7.39 (m, 1H), 7.27 (m,1H), 4.66 (m, 1H), 4.05 (s, 3H), 3.08-3.14 (m, 4H)

Example 319

Preparation ofN-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example291, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(4-chlorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 376.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.68 (s, 1H), 8.46 (d, J=1 Hz, 1H), 8.29 (d, J=1Hz, 1H), 7.27-7.34 (m, 4H), 4.57 (m, 1H), 4.21 (s, 3H), 3.25 (m, 2H),3.04 (m, 2H)

Example 320

Preparation ofN-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example292, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(4-chlorophenyl)propyl]carbamatefor 1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,4-difluorophenyl)propyl]carbamate.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 410.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 8.47 (s, 1H), 7.97 (s, 1H), 7.30 (m, 4H), 4.60 (m,1H), 4.03 (s, 3H), 3.22 (m, 2H), 3.00 (m, 2H).

Example 321

Preparation ofN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example261, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(3,5-difluorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate;The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 446.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 7.80 (s, 1H), 6.95 (m, 2H), 6.84 (m, 1H), 4.62 (m,1H), 4.04 (s, 3H), 3.20 (m, 2H), 3.01 (m, 2H).

Example 322

Preparation ofN-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to Example261, except substituting1,1-dimethylethyl[(2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-(4-chlorophenyl)propyl]carbamatefor 1,1-dimethylethyl((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate;The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 444.0 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 7.73 (s, 1H), 7.30 (m, 4H), 4.66 (m, 1H), 4.04 (s,3H), 3.18 (m, 2H), 2.99 (m, 2H).

Example 323

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamidea) 4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylic Acid

This intermediate was prepared according to the procedures of Example269 a) and b) except substituting1,4-dimethyl-5-(tributylstannanyl)-1H-1,2,3-triazole (from Preparation21) for 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole andsubstituting methyl 4-bromo-2-thiophenecarboxylate for methyl4-bromo-5-chloro-2-thiophenecarboxylate. LC-MS (ES) m/z 224.2 (M+H)⁺.

b)4-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

This intermediate was prepared according to the procedure of Example 269c) except substituting4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylic acid for5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylic acid,and substituting2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione for2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione. LC-MS (ES) m/z 504.2 (M+H)⁺.

c)5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

A solution of4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide(254 mg, 0.454 mmol), and NCS (60.6 mg, 0.454 mmol) inN,N-Dimethylformamide (DMF) (5 mL) to was heated at 40° C. overnight.The reaction mixture was taken into EtOAc, which was washed with H₂O 3×and brine, dried (Na₂SO₄) and concentrated. The residue was purified ona 25 g Biotage column, which was eluted with 50-100% EtOAc/hexane togive 76 mg (28%) of product as a white foamy solid and 63 mg ofrecovered starting material. LC-MS (ES) m/z 538.0 (M+H)⁺.

d)N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 269d), except substituting5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamidefor5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide.The final compound was purified by RP-HPLC, and converted to HCl saltwith 2N HCl aqueous solution. LC-MS (ES) m/z 408.2 (M+H)⁺, ¹H NMR(d₄-MeOH, 400 MHz) δ 7.88 (m, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.96 (m,1H), 4.65 (m, 1H), 4.10 (s, 3H), 3.21 (m, 2H), 3.03 (m, 2H), 2.06 (s,3H).

Example 324

Preparation ofN-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedures of Example 323 a), b) and d), except substituting4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamidefor5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide.LC-MS (ES) m/z 374.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.09 (d, J=1Hz, 1H), 8.06 (d, J=1 Hz, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 6.96 (m, 1H),4.56 (m, 1H), 4.20 (s, 3H), 3.23 (m, 2H), 3.05 (m, 2H), 2.47 (s, 3H).

Example 325

Preparation ofN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedures of Example 323 a), b) and d), except substituting2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dionefor2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.LC-MS (ES) m/z 392.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 8.13 (m, 2H),6.99 (m, 2H), 6.79 (m, 1H), 4.59 (m, 1H), 4.22 (s, 3H), 3.26 (m, 2H),3.06 (m, 2H), 2.49 (s, 3H).

Example 326

Preparation ofN-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 323, except substituting2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dionefor2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.LC-MS (ES) m/z 426.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 7.88 (s, 1H),6.96 (m, 2H), 6.82 (m, 1H), 4.62 (m, 1H), 4.07 (s, 3H), 3.22 (m, 2H),3.05 (m, 2H), 2.34 (s, 3H).

Example 327

Preparation ofN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to theprocedure of Example 323, except substituting substituting2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dionefor2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione.LC-MS (ES) m/z 426.2 (M+H)⁺, ¹H NMR (d₄-MeOH, 400 MHz) δ 7.87 (s, 1H),7.12-7.26 (m, 3H), 4.62 (m, 1H), 4.08 (s, 3H), 3.21 (m, 2H), 3.00 (m,2H), 2.36 (s, 3H).

Example 328

N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]-ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamidea) methyl 4-bromo-5-methyl-2-furancarboxylate

To a solution of methyl 4,5-dibromo-2-furancarboxylate (4.5 g, 15.85mmol) and BIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) CHLORIDE (0.38 g, 0.541mmol) in THF (100 mL) at RT was added chloro(methyl)zinc (15 mL, 30mmol) dropwise. After stirring for 10 h, the reaction was quenched withNH₄Cl (sat'd) (50 mL). The mixture was extracted with EtOAc (50 mL×3),and the collected organic layers were dried over MgSO₄. Solvent wasremoved under vacuum and the resulting residue was purified via columnchromatography (silica, EtOAc/Hex 10-20%) to give the title compound(2.5 g, 72%) as a white solid: LC-MS (ES) m/z 220 (M+H)⁺.

b) methyl 4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate

To a 100 mL sealed flask was added1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.2g, 9.91 mmol), potassium carbonate (2.84 g, 20.54 mmol), methyl4-bromo-5-methyl-2-furancarboxylate (1.5 g, 6.85 mmol) andBIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (0.175 g, 0.34 mmol) in1,2-dimethoxyethane (6 mL) and H₂O (1 mL). After stirring for 2 h at 72°C., the reaction solution was diluted with DCM (50 mL) and washed withH₂O. The organic layer was dried Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel [EtOAC/hexanes, 10-30%] to give theproduct [1.1 g, 68.6%] as an off white solid: LC-MS (ES) m/z 235 (M+H)⁺.

c) methyl4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate

A mixture of methyl4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (950 mg, 4.06mmol) and NCS (650 mg, 4.87 mmol) in THF (10 mL) was heated at 70° C. ina sealed tube. After 2 h, the reaction mixture was concentrated andpurified via column chromatography (silica, 10-20% EtOAc/Hexane)affording the title compound (970 mg, 89%) as a white solid: LC-MS (ES)m/z 269 (M+H)⁺.

d)4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-furancarboxamide

To a solution of methyl4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (500mg, 1.86 mmol) in THF/H₂O (5 mL/1 mL) was added KOH (500 mg, 8.91 mmol).The reaction mixture was heated to 50° C. for 4 h. The mixture wasconcentrated, diluted with H₂O (2 mL) and the pH was adjusted to 3. Themixture was extracted with DCM (10 mL×3). The collected organic layerswere concentrated under vacuum to give a crude acid (460 mg, 97%), whichwas used directly without of further purification: LC-MS (ES) m/z 255(M+H)⁺.

To the above acid (221 mg, 0.869 mmol) in DCM (5 mL) at 25° C. was addedPyBrOP (480 mg, 1.03 mmol) in one portion, followed by addition of DIPEA(1.0 mL, 5.73 mmol). After 10 min,2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione(250 mg, 0.79 mmol) was added to the reaction solution. After 1 h, thereaction mixture was concentrated and purified via column chromatography(silica, 30-50% EtOAc/Hexane) affording the title compound (401 mg, 92%)as a white solid: LC-MS (ES) m/z 553 (M+H)⁺.

e)N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

At rt, NH₂NH₂ (0.5 mL, 15.93 mmol) was added to4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-furancarboxamide(260 mg, 0.47 mmol) in MeOH (5 mL). After 48 h, the solvent was removedunder vacuum. The resulting residue was taken into DCM (20 mL), andwashed with H₂O (20 mL×3).

To the DCM solution was added HCl (36%, 10 mL, 120 mmol). After 1 h, theaqueous phase was separated, and washed with DCM (30 ml×3). Water wasremoved under high vacuum to give the title compound (140 mg, 69.7%) asan off-white solid: LC-MS (ES) m/z 423 (M+H)⁺, NMR (d₄-MeOD, 400 MHz) δppm 7.59 (s, 1H), 7.27-7.16 (m, 3H), 7.13-7.08 (m, 1H), 4.56 (m, 1H),4.06 (q, J=7.3 Hz, 2H), 3.26-3.22 (m, 1H), 3.17-3.11 (m, 1H), 3.05-3.00(m, 1H), 2.97-2.91 (m, 1H), 2.36 (s, 3H), and 1.33 (t, J=7.3 Hz, 3H).

Example 329 Capsule Composition

An oral dosage form for administering the present invention is producedby filing a standard two piece hard gelatin capsule with the ingredientsin the proportions shown in Table I, below.

TABLE I INGREDIENTS AMOUNTS N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-25 mg (1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (Compound ofExample 1) Lactose 55 mg Talc 16 mg Magnesium Stearate  4 mg

Example 330 Injectable Parenteral Composition

An injectable form for administering the present invention is producedby stirring 1.5% by weight ofN-(2-amino-1-phenylethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide(Compound of Example 2) in 10% by volume propylene glycol in water.

Example 331 Tablet Composition

The sucrose, calcium sulfate dihydrate and an Akt inhibitor as shown inTable II below, are mixed and granulated in the proportions shown with a10% gelatin solution. The wet granules are screened, dried, mixed withthe starch, talc and stearic acid, screened and compressed into atablet.

TABLE II INGREDIENTS AMOUNTS N-[2-amino-1-(phenylmethyl)ethyl]-5- 20 mg (1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (Compound of Example3) calcium sulfate dihydrate 30 mg  sucrose 4 mg starch 2 mg talc 1 mgstearic acid 0.5 mg  

While the preferred embodiments of the invention are illustrated by theabove, it is to be understood that the invention is not limited to theprecise instructions herein disclosed and that the right to allmodifications coming within the scope of the following claims isreserved.

1-41. (canceled)
 42. A compound selected from:N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;andN-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;or a pharmaceutically acceptable salt thereof.
 43. A compound of claim42 which is:N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;or a pharmaceutically acceptable salt thereof.
 44. A compound of claim42 which is:N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide.45. A compound of claim 42 which is:N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;or a pharmaceutically acceptable salt thereof.
 46. A compound of claim42 which is:N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide.47. A compound of claim 42 which is:N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide;or a pharmaceutically acceptable salt thereof.
 48. A compound of claim42 which is:N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide.49. A compound of claim 42 which is:N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;or a pharmaceutically acceptable salt thereof.
 50. A compound of claim42 which is:N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide.51.-52. (canceled)
 53. A pharmaceutical composition comprising acompound according to claim 42, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 54. A pharmaceuticalcomposition comprising a compound according to claim 43, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 55. A pharmaceutical composition comprising acompound according to claim 44 and a pharmaceutically acceptablecarrier.
 56. A pharmaceutical composition comprising a compoundaccording to claim 45, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 57. A pharmaceuticalcomposition comprising a compound according to claim 46 and apharmaceutically acceptable carrier.
 58. A pharmaceutical compositioncomprising a compound according to claim 47, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 59.A pharmaceutical composition comprising a compound according to claim 48and a pharmaceutically acceptable carrier.
 60. A pharmaceuticalcomposition comprising a compound according to claim 49, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 61. A pharmaceutical composition comprising acompound according to claim 50 and a pharmaceutically acceptablecarrier. 62.-63. (canceled)
 64. A process for preparing a pharmaceuticalcomposition containing a pharmaceutically acceptable carrier and acompound of claim 42 or a pharmaceutically acceptable salt thereof,which process comprises bringing the compound of claim 42, or apharmaceutically acceptable salt thereof, into association with apharmaceutically acceptable carrier.
 65. A method of treating a diseaseor condition selected from: cancer and arthritis, in a mammal in needthereof, which comprises administering to such mammal a therapeuticallyeffective amount of a compound of claim 42, or a pharmaceuticallyacceptable salt thereof.
 66. The method of claim 65 wherein the mammalis a human.
 67. The method according to claim 66 wherein said cancer isselected from: brain cancer (gliomas), glioblastomas, Bannayan-Zonanasyndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, coloncancer, head and neck cancer, kidney cancer, lung cancer, liver cancer,melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcomaand thyroid cancer.
 68. The method of inhibiting Akt activity in amammal in need thereof, which comprises administering to such mammal atherapeutically effective amount of a compound of claim 42, or apharmaceutically acceptable salt thereof.
 69. The method of claim 68wherein the mammal is a human.
 70. A method of treating cancer in ahuman in need thereof, which comprises: administering to such human atherapeutically effective amount of: a) a compound of claim 42, or apharmaceutically acceptable salt thereof; and b) at least oneanti-neoplastic agent.
 71. The method claim 70, wherein the at least oneanti-neoplastic agent is selected from the group consisting of:anti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,and cell cycle signaling inhibitors.
 72. The method of claim 70, whereinthe at least one anti-neoplastic agent is an anti-microtubule agentselected from diterpenoids and vinca alkaloids.
 73. The method of claim70, wherein the at least one anti-neoplastic agent is a diterpenoid. 74.The method of claim 70, wherein the at least one anti-neoplastic agentis a vinca alkaloid.
 75. The method of claim 70, wherein the at leastone anti-neoplastic agent is a platinum coordination complex.
 76. Themethod of claim 70, wherein the at least one anti-neoplastic agent ispaclitaxel, carboplatin, or vinorelbine.
 77. The method of claim 70,wherein the at least one anti-neoplastic agent is paclitaxel.
 78. Themethod of claim 70, wherein the at least one anti-neoplastic agent iscarboplatin.
 79. The method of claim 70, wherein the at least oneanti-neoplastic agent is vinorelbine.
 80. The method of claim 70,wherein the at least one anti-neoplastic agent is a signal transductionpathway inhibitor.
 81. The method of claim 80, wherein the signaltransduction pathway inhibitor is an inhibitor of a growth factorreceptor kinase selected from the group consisting of VEGFR2, TIE2,PDGFR, BTK, IGFR-1, TrkA, TrkB, TrkC, and c-fms.
 82. The method of claim80, wherein the signal transduction pathway inhibitor is an inhibitor ofa serine/threonine kinase selected from the group consisting of rafk,akt, and PKC-zeta.
 83. The method of claim 80, wherein the signaltransduction pathway inhibitor is an inhibitor of a serine/threoninekinase selected from the src family of kinases.
 84. The method of claim83, wherein the signal transduction pathway inhibitor is an inhibitor ofc-src.
 85. The method of claim 80, wherein the signal transductionpathway inhibitor is an inhibitor of Ras oncogene selected frominhibitors of farnesyl transferase and geranylgeranyl transferase. 86.The method of claim 80, wherein the signal transduction pathwayinhibitor is an inhibitor of a serine/threonine kinase selected from thegroup consisting of PI3K.
 87. The method of claim 70, wherein the atleast one anti-neoplastic agent is a cell cycle signaling inhibitor. 88.The method of claim 87, wherein the cell cycle signaling inhibitor isselected from inhibitors of the group CDK2, CDK4, and CDK6.
 89. Themethod according to claim 66 wherein said cancer is selected from: braincancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lungcancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone,thyroid cancer, Lymphoblastic T cell leukemia, Chronic myelogenousleukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilicleukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma,Immunoblastic large cell leukemia, Mantle cell leukemia, Multiplemyeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer.
 90. A method oftreating or lessening the severity of cancer, wherein said cancer isselected from: brain cancer (gliomas), glioblastomas, Bannayan-Zonanasyndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer,inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head andneck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovariancancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giantcell tumor of bone, thyroid cancer, Lymphoblastic T cell leukemia,Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cellleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia,Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia,Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim 43, or apharmaceutically acceptable salt thereof.
 91. A method of treating orlessening the severity of cancer, wherein said cancer is selected from:brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lungcancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone,thyroid cancer, Lymphoblastic T cell leukemia, Chronic myelogenousleukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilicleukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma,Immunoblastic large cell leukemia, Mantle cell leukemia, Multiplemyeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim
 44. 92. A methodof treating or lessening the severity of cancer, wherein said cancer isselected from: brain cancer (gliomas), glioblastomas, Bannayan-Zonanasyndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer,inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head andneck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovariancancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giantcell tumor of bone, thyroid cancer, Lymphoblastic T cell leukemia,Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cellleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia,Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia,Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim 45, or apharmaceutically acceptable salt thereof.
 93. A method of treating orlessening the severity of cancer, wherein said cancer is selected from:brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lungcancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone,thyroid cancer, Lymphoblastic T cell leukemia, Chronic myelogenousleukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilicleukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma,Immunoblastic large cell leukemia, Mantle cell leukemia, Multiplemyeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim
 46. 94. A methodof treating or lessening the severity of cancer, wherein said cancer isselected from: brain cancer (gliomas), glioblastomas, Bannayan-Zonanasyndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer,inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head andneck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovariancancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giantcell tumor of bone, thyroid cancer, Lymphoblastic T cell leukemia,Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cellleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia,Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia,Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim 47, or apharmaceutically acceptable salt thereof.
 95. A method of treating orlessening the severity of cancer, wherein said cancer is selected from:brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lungcancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone,thyroid cancer, Lymphoblastic T cell leukemia, Chronic myelogenousleukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilicleukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma,Immunoblastic large cell leukemia, Mantle cell leukemia, Multiplemyeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim
 48. 96. A methodof treating or lessening the severity of cancer, wherein said cancer isselected from: brain cancer (gliomas), glioblastomas, Bannayan-Zonanasyndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer,inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head andneck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovariancancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giantcell tumor of bone, thyroid cancer, Lymphoblastic T cell leukemia,Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cellleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia,Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia,Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim 49, or apharmaceutically acceptable salt thereof.
 97. A method of treating orlessening the severity of cancer, wherein said cancer is selected from:brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lungcancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone,thyroid cancer, Lymphoblastic T cell leukemia, Chronic myelogenousleukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilicleukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma,Immunoblastic large cell leukemia, Mantle cell leukemia, Multiplemyeloma Megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer, in a human inneed thereof, which comprises administering to such human atherapeutically effective amount of a compound of claim
 50. 98.-99.(canceled)
 100. A pharmaceutical composition according to claim 53,wherein the composition is in tablet form.
 101. A pharmaceuticalcomposition according to claim 54, wherein the composition is in tabletform.
 102. A pharmaceutical composition according to claim 55, whereinthe composition is in tablet form.
 103. A pharmaceutical compositionaccording to claim 56, wherein the composition is in tablet form.
 104. Apharmaceutical composition according to claim 57, wherein thecomposition is in tablet form.
 105. A pharmaceutical compositionaccording to claim 58, wherein the composition is in tablet form.
 106. Apharmaceutical composition according to claim 59, wherein thecomposition is in tablet form.
 107. A pharmaceutical compositionaccording to claim 60, wherein the composition is in tablet form.
 108. Apharmaceutical composition according to claim 61, wherein thecomposition is in tablet form. 109.-110. (canceled)